INTRODUCTION: Incretin-based medications (eg Ozempic, Mounjaro/Zepbound) have revolutionised the management of obesity, but their effects on fitness have not been reported. We report the effects of 24weeks treatment with tirzepatide, with and without concomitant resistance exercise, on fitness. METHODS: Participants, 50–70years with BMI≥30, or ≥27kg/m² with ≥1 comorbidity, were randomised to tirzepatide(T) with or without 3 sessions of resistance training/week at UWA (REX). Indices of aerobic fitness and body composition (DXA) were assessed at baseline and 24weeks. RESULTS: Exercise data are reported for 98 participants (T+NEX n=46♀20♂26; T+EX n=52♀24♂28). Body weight decreased significantly in both groups (T+NEX 99.9±15.3 to 81.8±14.9; T+EX 101.3±13.9 to 84.3±13.6kg, both P<0.001), with no significant difference between groups (Δ-17.5 vs -17.4kg, P=0.839). Fitness decreased in T+NEX (2.66±0.61 to 2.52±0.66L.min-1 P=0.003), no change occurred in T+EX (2.46±0.59 to 2.44±0.68L.min P=0.569), with significant difference between groups (T+NEX Δ-0.14; T+EX Δ-0.02L/min-1, P=0.041). Fitness normalised to body weight increased in both groups (T+NEX 27.1±6.3 to 30.9±6.9, P<0.001; T+EX 24.3±4.8 to 28.9±6.4ml.kg-1.min-1, P<0.001), with no difference between groups (Δ3.7 vs Δ4.7ml.kg-1.min-1, P=0.16). Normalised to total lean mass (n=44), fitness did not change in either group (T+NEX 48.4±5.2 to 47.9±4.8, P=0.458; T+EX 45.4±5.6 to 45.8±5.9ml.kgLBM-1.min-1, P=0.628), with no difference between groups (Δ-0.5 vs Δ0.4 ml.kgLBM-1.min-1, P=0.406). CONCLUSION: Tirzepatide induce large decreases in body weight in both groups. In absolute terms (L.min-1), aerobic fitness decreased as a result of T, but resistance training prevented this. When normalised for changes in body weight, both groups showed increases, with a larger impact in T+REX. Normalising for total body lean mass revealed a non-significant increase in T+EX, a decrease in T+NEX. These data provide a unique within-subject insight into the relevance of scaling fitness measures to body composition in humans, and indicate that undertaking exercise while on weight management medications is an important clinical goal.

Context: Subclinical thyroid dysfunction (ScTD) comprising subclinical hypothyroidism (SHypo) and subclinical hyperthyroidism (SHyper) has been associated with increased risk for cardiovascular events. Objective: To assess associations between ScTD and cardiovascular risk factors (cvRFs) according to age and sex. Design and setting: Pooled individual participant data analysis of large prospective cohort studies from the Thyroid Studies Collaboration. Participants: Aged 18 to 103 years with SHypo (TSH >4.50 mU/l, normal fT4) and SHyper (TSH <0.45 mU/l, normal fT4) vs. euthyroid (TSH 0.45-4.50 mU/l). Interventions: None as this is an observational study. Main outcome measures: cvRFs, i.e. blood pressure, lipid levels, hs-CRP. Results: Of 69,006 participants (mean age 62 years, 55% women, 25% current smokers) from 16 international cohorts, 3,748 (5.4%) had SHypo and 3,428 (5.0%) had SHyper. In both women and men, systolic and diastolic BP were similar regardless of thyroid status. Exceptions were lower diastolic BP in women with SHyper compared to euthyroids (adjusted mean difference [aMD] -1.3 mmHg, 95%CI -2.0 to -0.5), and lower systolic BP in men with SHyper compared to euthyroids (aMD -3.1 mmHg, 95%CI -4.8 to-1.4). In both women and men, lipid levels (total, HDL, LDL cholesterol, triglycerides) and hs-CRP were similar regardless of thyroid status. The only exception were women with SHyper who had a lower LDL cholesterol compared to euthyroids (aMD -0.17 mmol/l, 95%CI -0.29 to -0.05). Conclusions: Participants with ScTD and euthyroids have similar cvRFs and differences are arguably too small to explain the increased cardiovascular risk in ScTD observed in previous studies.

Diabetes mellitus is recognized as one of the most challenging health conditions facing all healthcare systems around the world and poses a high burden on individuals and society. Prevention of type 2 diabetes via screening programs and accessible, safe, and effective treatments would benefit people who might otherwise suffer decades of drug therapy and disease-related complications, leading to premature mortality, preventable morbidity, and significant economic burden. This study aimed to systematically map existing research on the cost-effectiveness of T2DM pharmaceutical treatment conducted alongside randomized controlled trials (RCT). This scoping review was carried out according to the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews" and "Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) " checklists. Medline, Health Medical Complete (ProQuest), Cochrane Central Register of Controlled Trials (CENTRAL), and Tufts Global Health Cost Effectiveness Analysis (GH CEA) Registries were searched from January 2010 to January 2023. 205 records were initially identified, and 21 records were selected for full-text review, resulting in the extraction and analysis of data from 13 articles, including 15 studies. Of the included studies, 53

Understanding the distribution and variation in NMR-based inflammatory markers is crucial to the evaluation of their clinical utility in disease prognosis and diagnosis. We applied high-resolution 1H NMR spectroscopy of blood plasma and serum to measure the acute phase reactive glycoprotein signals (GlycA and GlycB) and the subregions of the lipoprotein-based Supramolecular Phospholipid Composite signals (SPC1, SPC2, and SPC3) in a large multicohort population study. A total of 5702 samples were studied to determine the signal variations in a range of chronic and acute inflammatory conditions. We found that while GlycA and GlycB were increased in inflammation, the SPC regions behaved independently of Glyc signals, with SPC2 and SPC3 being reduced in chronic inflammation in comparison to healthy controls (p-value SPC2 = 2.9 × 10-10, p-value SPC3 = 2.2 × 10-3) and SPC1 (p-value = 0.29) being unchanged. SPC1 was decreased in acute inflammation, indicating a link to the immune response (p-value = 2.5 × 10-11). These findings confirm the independent biological relevance of all three SPC subregions and contraindicate the use of aggregate SPC values as general inflammatory markers.

Type 2 diabetes mellitus (T2DM) is a common metabolic disorder characterized by chronic hyperglycaemia, with physical inactivity and excessive adiposity as predisposing factors. This clinical trial aimed to investigate the effects of an exercise intervention on the metabolome of T2DM participants, fasting and in response to an oral glucose tolerance test (OGTT) and an acute exercise stimulus. Thirteen people with T2DM (age 51 ± 7 years; body mass index 32.7 ± 4.9 kg/m 2 ) completed 45 min of moderate‐intensity treadmill exercise on 12 days consecutively. Blood samples were collected before and after the first and last training sessions and during a pre‐ and postintervention OGTT. Fasted blood samples were collected from 198 healthy control subjects and 208 people with T2DM from an independent cohort for comparison. Samples were analysed using high‐resolution 1 H nuclear magnetic resonance spectroscopy and liquid chromatography–mass spectrometry. The exercise intervention did not induce a shift towards a healthier fasted metabolome in people living with T2DM. In response to consumption of a glucose bolus (OGTT), glycolysis‐related metabolites increased and free fatty acids decreased, with no effect of the exercise intervention. In response to acute exercise, glucose and amino acids decreased and free fatty acids increased, with similar responses on the last day of training as on the first day, indicating no effect of the intervention. The clinical trial was registered prospectively in the Australian New Zealand Clinical Trials Registry ACTRN12617000286347 on 24 February 2017.

Understanding the distribution and variation in inflammatory markers is crucial for advancing our knowledge of inflammatory processes and evaluating their clinical utility in diagnosing and monitoring acute and chronic disease. 1H NMR spectroscopy of blood plasma and serum was applied to measure a composite panel of inflammatory markers based on acute phase glycoprotein signals (GlycA and GlycB) and sub-regions of the lipoprotein derived Supramolecular Phospholipid Composite signals (SPC1, SPC2 and SPC3) to establish normal ranges in two healthy, predominantly white cohorts from Australia (n = 398) and Spain (n = 80; ages 20–70 years). GlycA, GlycB, SPC1 and SPC3 were not significantly impacted by age or sex, but SPC2 (an HDL-related biomarker) was significantly higher in women across all age ranges by an average of 33.7%. A free-living Australian population cohort (n = 3945) was used to explore the relationship of BMI with the panel of inflammatory markers. The glycoprotein signals were directly associated with BMI with GlycB levels being significantly higher for women in all BMI classes. Conversely, SPC2 was found to be inversely associated with BMI and differed significantly between the sexes at each BMI category (normal weight p = 3.46x10-43, overweight p = 3.33x10-79, obese p = 2.15x10-64). SPC1 and SPC3 were markedly less affected by BMI changes. Given the significant association between SPC2 and sex, these data suggest that men and women should be modelled independently for NMR-determined inflammatory biomarkers, or that data should be corrected for sex.

BACKGROUND:Aboriginal and Torres Strait Islander (Indigenous) Australians experience a disproportionately higher prevalence of obesity compared with non-Indigenous Australians. We aimed to describe existing research into lifestyle, pharmacological or surgical interventions for preventing or treating obesity in Indigenous Australians. METHODS:A systematic review of published and grey literature was performed. Medline, Embase, Emcare (on the OVID platform), Web of Science and website searches were conducted to April 2024. Observational and randomised studies of adult Indigenous Australians were included if an intervention was implemented to prevent and/or treat obesity and post-intervention results were reported. The PRISMA systematic review reporting methods was used to collate data. RESULTS:Of 1019 records screened, 17 were included; most described educational initiatives or lifestyle programs for improving diet and exercise. There were no reports of pharmacotherapies for weight management. The effect of lifestyle programs on weight reduction was modest (∼2-4 kg after 4-12 months). There were five reports on short-term (12 week) structured exercise programs. Two non-randomised studies of structured exercise showed reduction in weight in the highest weight groups whilst the two randomised trials showed ∼2 kg weight reduction compared with control. One observational study described mean ∼26 kg weight reduction at two years after laparoscopic adjustable gastric banding in 26 Indigenous Australians. CONCLUSIONS:Community-based lifestyle interventions to manage excess weight can be successfully conducted in Indigenous Australians, but with generally limited efficacy. Providing background community-based lifestyle programs may facilitate the conduct of randomised trials of newer, effective anti-obesity pharmacotherapy in this high priority population.

Context The combined effects of testosterone treatment and lifestyle intervention on sexual function in men at high risk of type 2 diabetes are unclear.Objective To assess the effect of testosterone treatment with a lifestyle intervention in men aged 50 to 74 years at high risk of, or newly diagnosed with, type 2 diabetes (via oral glucose tolerance test).Design A secondary analysis of the Testosterone for the Prevention of Type 2 Diabetes trial, a double-blind, placebo-controlled trial conducted across 6 Australian centers.Interventions Intramuscular testosterone undecanoate (1000 mg) or placebo, 3 monthly for 2 years alongside a community-based lifestyle program.Main outcomes Sexual function measured using the International Index of Erectile Function (IIEF)-15 questionnaire.Results Of 1007 participants, 792 (79%) had complete International Index of Erectile Function-15 data. Baseline domain scores were inversely related to age and waist circumference, but unrelated to serum testosterone or estradiol levels. Testosterone treatment improved all 5 International Index of Erectile Function-15 domain scores, with stronger effects on sexual desire and orgasmic function in older men, and sexual desire in men with higher depression scores. Testosterone had no impact on depression. Independent of treatment, reductions in waist circumference were associated with improved erectile function, and reductions in depression scores correlated with better sexual function. Clinically significant improvement in erectile function and sexual desire occurred in 3% and 10% of men, respectively, and was inversely related to baseline function. Clinically significant improvement improvements in erectile function and sexual desire were greater in younger and older men respectively.Conclusion Testosterone treatment enhanced sexual desire and, to a lesser extent, erectile function, particularly in older men and those with higher waist circumference or depressive symptoms. Reduced waist circumference and depression independently improved sexual function.

BACKGROUND:The influence of testosterone on risk for cardiovascular events in men is uncertain. Previous observational studies of sex hormones and incident cardiovascular disease in men have reported inconsistent findings, limited by cohort sizes and different selection criteria. OBJECTIVE:To analyze associations of serum total testosterone and sex hormone-binding globulin (SHBG) with incident cardiovascular events in men. DESIGN:Cohort study. SETTING:UK Biobank prospective cohort. PARTICIPANTS:Community-dwelling men aged 40 to 69 years. MEASUREMENTS:Testosterone and SHBG were assayed, and free testosterone was calculated. Cox proportional hazards regression was done, with outcomes of incident myocardial infarction (MI), hemorrhagic stroke (HS), ischemic stroke (IS), heart failure (HF), and major adverse cardiovascular events (MACE), adjusted for sociodemographic, lifestyle, and medical factors. RESULTS:Of 210 700 men followed for 9 years, 8790 (4.2%) had an incident cardiovascular event. After adjustment for key variables, lower total testosterone concentrations (quintile 1 vs. quintile 5) were not associated with incident MI (fully adjusted hazard ratio [HR], 0.89 [95% CI, 0.80 to 1.00]), HS (HR, 0.94 [CI, 0.70 to 1.26]), IS (HR, 0.95 [CI, 0.82 to 1.10]), HF (HR, 1.15 [CI, 0.91 to 1.45]), or MACE (HR, 0.92 [CI, 0.84 to 1.00]). Men with lower calculated free testosterone values had a lower incidence of MACE (HR, 0.90 [CI, 0.84 to 0.97]). Lower SHBG concentrations were associated with higher incidence of MI (HR, 1.23 [CI, 1.09 to 1.38]) and lower incidence of IS (HR, 0.79 [CI, 0.67 to 0.94]) and HF (HR, 0.69 [CI, 0.54 to 0.89]), but not with HS (HR, 0.81 [CI, 0.57 to 1.14]) or MACE (HR, 1.01 [CI, 0.92 to 1.11]). LIMITATION:Observational study; single baseline measurement of testosterone and SHBG. CONCLUSION:Men with lower total testosterone concentrations were not at increased risk for MI, stroke, HF, or MACE. Calculated free testosterone may be associated with risk for MACE. Men with lower SHBG concentrations have higher risk for MI but lower risk for IS and HF, with causality to be determined. PRIMARY FUNDING SOURCE:Western Australian Health Translation Network, Medical Research Future Fund, and Lawley Pharmaceuticals.

BACKGROUND:Pooled quality control (PQC) samples are the gold standard for data quality monitoring in metabolic phenotyping studies. Typically composed of equal parts from all study samples, PQCs can be challenging to generate in large cohorts or when sample volumes are low. As an alternative, externally sourced matrix-matched surrogate QCs (sQC) have been proposed. This study evaluates the performance of sQCs against PQCs for assessing analytical variation, data pre-processing, and downstream data analysis in a targeted lipidomics workflow. RESULTS:Plasma samples (n = 701) from the Microbiome Understanding in Maternity Study, along with PQC (n = 80) and sQC (n = 80) samples, were analyzed using a lipidomics assay targeting 1162 lipids. QC samples were injected throughout acquisition, and data pre-processing was performed using each strategy. For simplicity, a subset (n = 381) of the study samples was used to assess differences in downstream statistical analyses. Both QC approaches demonstrated high analytical repeatability. While PQC and sQC compositions differed, use of PQCs retained less than 4 % more lipid species during pre-processing. Univariate analysis identified more statistically significant lipids with PQC-based pre-processing, but multivariate model performance was similar between datasets. SIGNIFICANCE:This study provides a comprehensive comparison of QC strategies and emphasizes the importance of careful QC workflow selection. While PQCs offer advantages, sQCs serve as a suitable alternative for quality assessment and pre-processing. Their commercial availability also supports use as intra- and inter-laboratory long-term references, aiding data harmonization across studies and laboratories.

Objective We have shown that men aged 50 years+ at high risk of type 2 diabetes treated with testosterone together with a lifestyle program reduced the risk of type 2 diabetes at 2 years by 40% compared to a lifestyle program alone. To develop a personalized approach to treatment, we aimed to explore a prognostic model for incident type 2 diabetes at 2 years and investigate biomarkers predictive of the testosterone effect.Design Model development in 783 men with impaired glucose tolerance but not type 2 diabetes from Testosterone for Prevention of Type 2 Diabetes; a multicenter, 2-year trial of Testosterone vs placebo. External validation performed in 236 men from the Examining Outcomes in Chronic Disease in the 45 and Up Study (EXTEND-45, n = 267 357).Methods Type 2 diabetes at 2 years defined as 2-h fasting glucose by oral glucose tolerance test (OGTT) >= 11.1 mmol/L. Risk factors, including predictive biomarkers of testosterone treatment, were assessed using penalized logistic regression.Results Baseline HbA1c and 2-h OGTT glucose were dominant predictors, together with testosterone, age, and an interaction between testosterone and HbA1c (P = .035, greater benefit with HbA1c >= 5.6%, 38 mmol/mol). The final model identified men who developed type 2 diabetes, with C-statistics 0.827 in development and 0.798 in validation. After recalibration, the model accurately predicted a participant's absolute risk of type 2 diabetes.Conclusions Baseline HbA1c and 2-h OGTT glucose predict incident type 2 diabetes at 2 years in high-risk men, with risk modified independently by testosterone treatment. Men with HbA1c >= 5.6% (38 mmol/mol) benefit most from testosterone treatment, beyond a lifestyle program.

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.

Abstract Disclosure: M. Umapathysivam: None. S. Nawaz: None. K. Robledo: None. C.A. Allan: None. K. Bracken: None. M. Grossmann: None. D.J. Handelsman: None. W.J. Inder: None. D. Jesudason: None. B. Stuckey: None. B. Yeap: None. A. Januszewski: None. A. Jenkins: None. A. Conway: None. B. Hastoy: None. G.A. Wittert: Consulting Fee; Self; I-Nova. Grant Recipient; Self; Lawley pharmaceuticals, Bayer, Weight Watchers, Eli Lilly & Company. Speaker; Self; Bayer, Inc., Amgen Inc, Besin Health Care. Background: In the Testosterone for the prevention of type 2 diabetes (T4DM) Study, treatment with testosterone (T)-undecanoate (1000 mg IM 3 monthly) vs placebo decreased fat mass and reduced the risk of T2D by 40% after 2 years. However, the mechanism(s) by which T therapy prevents or reverts T2D remain unclear. Aim: To assess (1) the impact of T treatment on insulin resistance (IR) and beta-cell function in the T4DM study and (2) the in-vitro effect of graded T exposure on glucose stimulated insulin secretion (GSIS) from the human beta-cell line EndoC-βH1. Methods: (1) T4DM study: Men (n= 1007) from the T4DM study aged, 50-74 years, waist circumference (WC) >95cm, with prediabetes, or newly diagnosed T2D (by OGTT) and serum testosterone (T) ≤ 14 nmol/L (chemiluminescent assay) treated with T-undecanoate (1000 mg IM 3 monthly) or placebo for 2 years. Men were included if they had fasting bloods at baseline, weeks 18, 66, and 102 (N=743). We compared the change in glycated albumin, and derived measures of beta-cell function (HOMA2-B) and insulin resistance (HOMA-IR) using fasting glucose and c-peptide in T and placebo treated men using linear regression models.(2) EndoC-βH1 were incubated with T 5nM, 10nM and 15nM for 20 min and 15nM T for 2-days. Insulin secretion and content were measured at baseline (1mM glucose) and after 20 min exposure 20mM glucose. Results: Treatment with T compared to placebo reduced glycated albumin (-3.4 umol/L; 95%CI:1.4-5.4, p<0.001) maximally at week 66, along with C-peptide (corrected for baseline C-peptide and change in fasting glucose) (-0.12 nmol/L;-0.22,-0.02; p=0.01), HOMA2-B (-6.1; 95%CI: -16, 3.7; p=0.2) and HOMA-IR (-0.20; 95%CI: -0.59,0.20; p=0.3). In-vitro, acute exposure of EndoC-βH1 to 5nM and 10nM of T had no effect on GSIS, and 15nM T reduced GSIS (<20%, p=0.002). T, at 15nM for 2 days was without effect on GSIS. EndoC-βH1 insulin content was not altered at any concentration or timeframe of T exposure. Conclusion: In men with pre-diabetes or early T2D, T treatment reduces glycemia without evidence either in vivo or in-vitro of an affect to increase insulin secretion. Presentation: 6/1/2024

Background: An inverse relationship exists between inflammation and testosterone concentrations in non-inflammatory bowel disease (IBD) immune conditions but has not been objectively explored in the IBD male population. We aimed to characterize the distribution of testosterone concentrations in a cohort of males with IBD and identify any relationship between testosterone levels and disease activity. Methods: We conducted a prospective cross-sectional study of male IBD patients. Demographics, disease characteristics, sex-hormone concentration, gonadotropins, C-reactive protein, fecal calprotectin, and patient-reported outcomes on quality of life and erectile function were collected. Relationships between disease activity, biomarkers, patient-reported outcome scores, and testosterone levels were analyzed using univariate and multivariate linear regression analyses. Results: A total of 85 male IBD patients were included with a mean age 44 +/- 14.1 years, of which 49.4% had Crohn's disease. Mean testosterone concentration was 15.4 +/- 5.2 nmol/L and 17.6% had a serum testosterone <10.4 nmol/L. Active disease was associated with lower testosterone concentrations in univariate analysis (beta +/- SE = -0.25 +/- -1.99, P = .02) but not in multivariate analysis (beta -0.18 +/- 1.75, P = .06). Testosterone concentrations were independently associated with sex hormone-binding globulin levels (beta +/- SE = 0.45 +/- 0.04, P < .0001) and a younger age (beta +/- SE = -0.32 +/- 0.04, P <.0001). Erectile function scores (5-item International Index of Erectile Function) were lower in IBD patients with a longer duration of disease (beta +/- SE = -0.24 +/- 0.006, P = .04). Conclusions: Lower testosterone concentrations in men with IBD may reflect confounding from other factors and are not independently associated with disease activity. Greater awareness and screening for sexual dysfunction should occur in males with IBD, particularly in those with a longer disease duration. Lay Summary Sexual dysfunction in men with inflammatory bowel disease (IBD) is multifactorial. We explored the underlying hormonal profile of men with IBD and characterized the distribution of testosterone levels. Almost 1 in 5 males with IBD have a level that is considered low by international definitions (<10.4 nmol/L).

Objective: Sociodemographic, lifestyle, and medical variables influence total testosterone (T) and sex hormone-binding globulin (SHBG) concentrations. The relationship between these factors and "free" T remains unclear. We examined 21 sociodemographic, lifestyle, and medical predictors influencing calculated free T (cFT) in community-dwelling men across ages. Design: This is a cross-sectional analysis in 20 631 participants in the Androgens in Men Study. Methods: Individual participant data (IPD) were provided by 9 cohorts. Total T was determined using mass spectrometry, SHBG using immunoassays, and cFT using the Vermeulen formula. Associations were analyzed using 2-stage random effects IPD meta-analyses. Results: Cohort median ages ranged from 40 to 76 years and median cFT concentrations from 174.3 to 422.8 pmol/L. In men aged 17-99 years, there was a linear inverse association of cFT with age (-57.2 pmol/L [95% confidence interval, -69.4, -44.9] per 1 SD increase in age). Calculated free T increased with increasing baseline body mass index (BMI) among men with BMI < 23.6 kg/m2 , but decreased among men with BMI > 23.6 kg/m2 (-24.7 pmol/L [-29.1, -20.3] per 1 SD increase in the 25.4-29.6 kg/m2 BMI range). Calculated free T was lower in younger men, who were married or in a de facto relationship (-18.4 pmol/L [-27.6, -9.3]) and in men who formerly smoked (-5.7 pmol/L [-8.9, -2.6]), were in poor general health (-14.0 pmol/L [-20.1, -7.8]), and had diabetes (-19.6 pmol/L [-23.0, -16.3]), cardiovascular disease (-5.8 pmol/L [-8.3, -3.2]), or cancer (-19.2 pmol/L [-24.4, -14.1]) Conclusions: Calculated free T was most prominently associated with age and BMI. The linear, inverse association with age, nonlinear association with BMI, and presence of diabetes, cancer, and sociodemographic factors should be considered when interpreting cFT values.

Purpose of review Lower testosterone concentrations have been associated with poorer health outcomes in ageing men, but proving causality and demonstrating potential for therapeutic benefit requires randomized clinical trials (RCTs). This review discusses recent observational findings and results of major testosterone RCTs, to explore the need for another, larger trial. Recent findings Evidence of Leydig cell impairment emerges in men above the age of 70 years. Lower testosterone is associated with diabetes risk, and also risk of incident dementia. An individual participant data meta-analysis found that below thresholds of testosterone of 7.4 nmol/L and 5.3 nmol/l respectively, risks of all-cause mortality and cardiovascular deaths in men increased. Testosterone for the Prevention of Type 2 Diabetes Mellitus (T4DM), a multicentre RCT, showed that testosterone treatment prevented or reverted type 2 diabetes in men at high risk. Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE), a cardiovascular safety trial, demonstrated cardiovascular and prostate safety of testosterone treatment in men with or at risk of cardiovascular disease. T4DM confirmed findings from the Testosterone Trials (T-Trials) that testosterone improved sexual function, and bone microarchitecture and density. However, in TRAVERSE, testosterone-treated men had a higher risk of clinical bone fractures, but not major osteoporotic fractures. Summary Men with disorders of the hypothalamic–pituitary–testicular (HPT) axis causing androgen deficiency warrant consideration for testosterone therapy. In men with an intact HPT axis, testosterone treatment is a pharmacological intervention which requires justification from high quality RCT data. Currently, there is insufficient evidence to justify wider use of testosterone for prevention of cardiometabolic disease. However, there is scope for another large testosterone RCT to investigate whether testosterone treatment might, in older men, extend disability-free survival.

Testosterone therapy for men with hypogonadism due to identifiable hypothalamic-pituitary-testicular (HPT) pathology is uncontroversial. However, the risks and benefits of testosterone for men with clinical features of hypogonadism in the absence of identifiable HPT axis pathology have been uncertain. Recent landmark placebo-controlled trials assessed the benefits and risks of testosterone therapy (≤3 years) for middle-aged and older men with symptoms and possible signs of hypogonadism or end-organ androgen deficiency, low or low-normal serum testosterone concentrations, but no HPT pathology: Testosterone therapy (1) had modest-but clinically significant-benefits on average self-reported energy and mood, sexual function, and satisfaction; (2) in conjunction with a lifestyle programme, reversed or reduced incident type 2 diabetes mellitus (T2D) in men at high risk of or newly diagnosed with T2D; (3) modestly improved objectively assessed muscle strength and timed walking distance; (4) increased bone density and strength, but did not reduce falls or typical osteoporotic fractures and surprisingly increased the risk of fractures typically attributable to trauma; and (5) did not significantly increase the risk of myocardial infarction, stroke, or prostate cancer. These landmark trials help to inform clinical decision-making about testosterone therapy for men.

Aims: Psychological interventions have had modest effects on HbA1c in adults with Type 1 diabetes (T1D). We evaluated a novel behaviour therapy (BT) group program aiming to improve diabetes self-care and reduce HbA1c and distress. Core features were the application of a functional-analytic model, behavioural self-management training, and personally selected T1D self-care behaviours as treatment targets. Methods: Participants with T1D, 2-consecutive HbA1c >= 8.5 %(69 mmol/mol) and/or diabetes-related emotional/behavioural difficulties who had received specialist multidisciplinary input for >= 2 years completed 6-sessions of BT over 9-weeks. Outcomes were assessed at baseline, on completing 5-consecutive weekly sessions (post-) and at session 6, 1-month after (follow-up). Results: Of 66 participants mean age 37.9 years, mean age at T1D diagnosis 22.0 years, and median T1D duration 14 years, 54 completed BT. HbA1c improved from baseline to follow-up (9.7 +/- 1.9 %-8.8 +/- 1.3 %, p < 0.001), as did diabetes distress (DD: total score 49.2 +/- 7.8 baseline, 38.9 +/- 14.7 post- and 32.8 +/- 11.7 follow-up, p < 0.001). All DD subscales of emotional burden, and physician, regimen, and interpersonal distress, improved (p < 0.001). Consistent results were observed for patients on multiple daily injections and continuous subcutaneous insulin infusion therapy. Conclusions: BT based on a functional-analytic and behavioural self-management model holds promise as an effective means of improving HbA1c and reducing DD in adults with T1D.