Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. To clarify associations of sex hormones with these outcomes. Systematic literature review to July 2019, with bridge searches to March 2024. Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. 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. 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. Observational study design, heterogeneity among studies, and imputation of missing data. 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. Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Purpose: Insomnia symptoms and sleep apnea frequently co-occur and are associated with worse sleep, daytime function, mental health and quality of life, compared to either insomnia or obstructive sleep apnea (OSA) alone. This study aimed to investigate the association of symptoms of co-morbid insomnia and sleep apnea (COMISA) with all-cause mortality. Patients and Methods: Wisconsin Sleep Cohort data were analysed to assess potential associations between COMISA symptoms and all-cause mortality. Nocturnal insomnia symptoms were defined as difficulties initiating sleep, maintaining sleep, and/or early morning awakenings “often” or “almost always”, and/or regular sedative-hypnotic medicine use. OSA was defined as an apnea-hypopnea index ≥ 5/hr sleep. Participants were classified as having neither insomnia symptoms nor OSA, insomnia symptoms alone, OSA alone, or COMISA symptoms. Associations between the four groups and all-cause mortality over 20 years of follow-up were examined via multivariable adjusted Cox regression models. Results: Among 1115 adult participants (mean ± SD age 55 ± 8 years, 53% males), 19.1% had COMISA symptoms. After controlling for sociodemographic and behavioral factors, COMISA symptoms were associated with an increased risk of all-cause mortality compared to no insomnia symptoms or OSA (HR [95% CI]; 1.71 [1.00– 2.93]). OSA alone (0.91 [0.53, 1.57]) and insomnia symptoms alone (1.04 [0.55, 1.97]) were not associated with increased mortality risk. Conclusion: Co-morbid insomnia symptoms and sleep apnea is associated with increased all-cause mortality risk. Future research should investigate mechanisms underpinning COMISA and the effectiveness of different treatment approaches to reduce mortality risk for this common condition.

Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. To clarify factors associated with variations in sex hormone concentrations. Systematic literature searches (to July 2019). Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. 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. 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. Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. 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. Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Introduction: Estimating insomnia prevalence in epidemiological studies is hampered by variability in definitions and interpretation of criteria. We addressed the absence of a population-based estimate of insomnia in Australia using the widely accepted contemporary International Classification of Sleep Disorders (ICSD-3) criteria, which includes sleep opportunity, and has not been applied in studies to date. Consistent use of these criteria across epidemiological studies, however, requires evidence of the clinical utility of a sleep opportunity criterion for targeting strategies. Methods: A cross-sectional national on-line survey (2019 Sleep Health Foundation Insomnia Survey) of Australian adults (18– 90 years, n = 2044) was conducted. Chronic insomnia was defined as sleep symptoms and daytime impairment experienced ≥ 3 times per week, and present for ≥ 3 months, with adequate sleep opportunity (time in bed (TIB) ≥ 7.5 hrs). Self-rated general health (SF-1) and ever diagnosed health conditions (including sleep disorders) were assessed. Results: Chronic difficulties initiating and maintaining sleep and daytime symptoms (n = 788) were more common in females (41.5%) than males (35.3%), p = 0.004. Excluding participants reporting frequent pain causing sleep disruption and TIB < 7.5 hrs generated an insomnia disorder estimate of 25.2% (95% CI: 22.5– 28.2) in females and 21.1% (18.4– 23.9) in males [23.2% (21.2– 25.2) overall]. This compares with 8.6% (7.3– 10.0) with insomnia symptoms and TIB < 7.5 hrs and 7.5% (6.4– 8.7%) ever diagnosed with insomnia. Insomnia symptom groups with TIB < 7.5 and ≥ 7.5 hours demonstrated similar odds of reporting fair/poor health [odds ratio (OR): 3.2 (95% CI: 2.1– 4.8) and 2.9 (95% CI: 2.2– 3.9) respectively], ≥ 1 mental health condition, ≥ 1 airway disease, and multimorbidity. Conclusion: Adults with significant sleep and daytime symptomatology and TIB < 7.5 hrs did not differ clinically from those with insomnia disorder. Consideration of criteria, particularly adequate sleep opportunity, is required to consistently identify insomnia, and establish health correlates in future epidemiological studies. Further evaluation of the clinical utility of the sleep opportunity criterion is also required.

Purpose: We aimed to estimate the prevalence of probable shift work disorder (pSWD) in a representative sample of Australian workers and identify sleep, health and safety correlates. Patients and Methods: In 2019, data were collected from working respondents as part of a cross-sectional national sleep health survey conducted online (n=964 total; n=448 individuals on non-standard work schedules). We established the prevalence of pSWD according to International Classification of Sleep Disorders criteria (ICSD-R, ICSD-2 and ICSD-3). Poisson regression was used to determine crude and adjusted prevalence association (prevalence ratio, PR) of pSWD with sleep, health and safety outcomes. Results: Overall prevalence of pSWD in workers on non-standard work schedules was 10.5%, ranging from 9.6% in early morning workers to 12.7% in rotating shift workers. In adjusted models, workers who met the criteria for pSWD were 1.8 times more likely to report both depression/bipolar disorder, and anxiety/panic disorder, and 1.7 times more likely to report work errors due to a sleep problem. Conclusion: The prevalence of pSWD in employees engaged in non-standard work schedules is influenced by selection of factors used to quantify pSWD, including sleep/wake patterns. Higher likelihoods of mental health problems and workplace errors in those with pSWD highlight the importance of intervention and management of this under-recognised sleep disorder.