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The role of the anti-Müllerian hormone (AMH) as an indicator of physical and reproductive health in men is unclear. We assessed the relationships between AMH and follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and metabolic parameters, in a cohort of expectant fathers.ORIGINS Project prospective cohort study.Community-dwelling men.Partners of pregnant women attending antenatal appointments.Serum AMH, FSH, LH, testosterone, and metabolic parameters.In 485 expectant fathers, median age 33 years, median AMH was 40 pmol/L (quartiles 29, 56). AMH was inversely correlated with FSH, age, and body mass index (BMI) (correlation coefficients: -.32, -.24, and -.17 respectively). The age association was nonlinear, with peak AMH between 20 and 30 years, a decline thereafter, and somewhat steady levels after 45 years. The inverse association of AMH with FSH was log-linear and independent of age and BMI (β: -.07, SE: 0.01, p lt; .001). AMH was inversely correlated with waist circumference and directly associated with sex hormone-binding globulin. Testosterone was moderately correlated with AMH (correlation coefficient: .09, β: .011, SE: 0.004, p = .014): this association was mediated by an inverse relationship with BMI (mediated proportion 0.49, p lt; .001).In reproductively active men, lower AMH is a biomarker for advancing age, and for poorer metabolic and reproductive health. The inverse association between AMH and FSH is independent of age and BMI, whereas the association of AMH and testosterone is mediated via BMI. The utility of AMH to predict reproductive and cardiometabolic outcomes in men warrants further investigation.

Middle-aged and older men with lower testosterone concentrations are more likely to have or to develop metabolic syndrome and type 2 diabetes. Central adiposity is a risk factor for metabolic syndrome and diabetes and predisposes to lower testosterone concentrations. Conversely, testosterone treatment reduces fat mass and insulin resistance. In a randomized controlled trial of 1007 men with either impaired glucose tolerance or newly diagnosed type 2 diabetes, 2 years of testosterone treatment on a background of lifestyle intervention reduced the risk of type 2 diabetes by 40%; this demonstrates the potential utility for testosterone pharmacotherapy to prevent diabetes in men.

Objective To determine if hearing loss is associated with increased risk of frailty in later life. Study design Cross-sectional study of a community sample of 4,004 men aged 70 years and above living in the metropolitan region of Perth, Western Australia. Data were retrieved from the Health in Men Study (HIMS) and the Western Australian Data Linkage System (WADLS). Frailty was assessed using the FRAIL scale and the Frailty Index. Hearing loss was defined by self-report or by diagnosis recorded in the WADLS. We also collected demographic, lifestyle and social support information. Main outcome measures Frailty was assessed using the FRAIL scale and the Frailty Index. Results The prevalence of frailty in the sample population was 16.1% and 25.4% when assessed using the FRAIL scale and the Frailty Index respectively. After adjusting for participant demographic, lifestyle and social factors, hearing loss was significantly associated with the prevalence of frailty when diagnosed by either measure (FRAIL scale: odds ratio [OR] 1.59, 95 CI% 1.32 to 1.91; Frailty Index: OR 1.76, 95 CI% 1.50 to 2.05). The proportion of men with hearing loss increased with increasing severity of frailty. Conclusion Hearing loss is associated with increased prevalence of frailty in older men when assessed using the FRAIL scale and the Frailty Index. Future longitudinal studies using objective measures of hearing will be helpful in determining if this association is likely to be causal.

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.To analyze associations of serum total testosterone and sex hormone-binding globulin (SHBG) with incident cardiovascular events in men.Cohort study.UK Biobank prospective cohort.Community-dwelling men aged 40 to 69 years.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.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]).Observational study; single baseline measurement of testosterone and SHBG.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.Western Australian Health Translation Network, Medical Research Future Fund, and Lawley Pharmaceuticals.

The association of testosterone concentrations with dementia risk remains uncertain. We examined associations of serum testosterone and sex hormone-binding globulin (SHBG) with incidence of dementia and Alzheimer's disease.Serum total testosterone and SHBG were measured by immunoassay. The incidence of dementia and Alzheimer's disease (AD) was recorded. Cox proportional hazards regression was adjusted for age and other variables.In 159,411 community-dwelling men (median age 61, followed for 7 years), 826 developed dementia, including 288 from AD. Lower total testosterone was associated with a higher incidence of dementia (overall trend: P = .001, lowest vs highest quintile: hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.13-1.81), and AD (P = .017, HR = 1.80, CI = 1.21-2.66). Lower SHBG was associated with a lower incidence of dementia (P .001, HR = 0.66, CI = 0.51-0.85) and AD (P = .012, HR = 0.53, CI = 0.34-0.84).Lower total testosterone and higher SHBG are independently associated with incident dementia and AD in older men. Additional research is needed to determine causality.

Background: The relationship between testosterone and cancer is relatively unexplored. We sought to examine whether testosterone and related hormones are associated with incident prostate, lung, and colorectal cancer.Methods: This was a population-based cohort study. Demographic and clinical predictors of cancer, and testosterone, sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) were measured between 2001 and 2004 in 3,635 community-dwelling men aged 70 to 88 years (mean 77 years). Cancer notifications were obtained via electronic record linkage until December 31, 2010.Results: During a mean follow-up period of 6.7 ± 1.8 years, there were 297, 104, and 82 cases of prostate, colorectal, and lung cancer. In adjusted competing risks proportional hazards models, each one SD increase in free testosterone was associated with a 9% increase in prostate cancer risk (95% confidence interval [CI], 1.00–1.18), but other hormones were not significantly associated. No significant associations were observed between hormonal parameters and colorectal cancer. Higher total testosterone was associated with lung cancer. Compared with the mean of 15 nmol/L, men with levels of 20 nmol/L were 1.38 times more likely to be cases (95% CI, 1.21–1.57), whereas those with levels of 30 nmol/L were 3.62 times more likely to be cases (95% CI, 2.53–5.18). Higher free testosterone was also associated with lung cancer, though SHBG and LH were not. Associations were maintained after exclusion of current smokers.Conclusions: Higher free testosterone was associated with incident prostate cancer. Higher testosterone levels may also be associated with lung cancer.Impact: Further studies should investigate whether these risks apply to men receiving testosterone therapy. Cancer Epidemiol Biomarkers Prev; 21(8); 1319–29. ©2012 AACR.

PDF file - 94K, Competing-risks proportional hazards models exploring associations between hormonal parameters (categorised at the quintiles) and incident prostate cancer

Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13–1.31; P trend < 0.001). However, this association varied by disease aggressiveness (Pheterogeneity = 0.014); higher circulating 25(OH)D was associated with a higher risk of nonaggressive disease (OR per 80 percentile increase = 1.24, 1.13–1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78–1.15). 1,25(OH)2D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias.Significance:This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease.

Middle-aged and older men have typically accumulated comorbidities, are increasingly sedentary, and have lower testosterone concentrations (T) compared to younger men. Reduced physical activity (PA) and lower T both are associated with, and may predispose to, metabolically adverse changes in body composition, which contribute to higher risks of cardiometabolic disease. Exercise improves cardiometabolic health, but sustained participation is problematic. By contrast, rates of T prescription have increased, particularly in middle-aged and older men without organic diseases of the hypothalamus, pituitary, or testes, reflecting the unproven concept of a restorative hormone that preserves health. Two recent large randomized trials of T, and meta-analyses of randomized trials, did not show a signal for adverse cardiovascular (CV) events, and T treatment on a background of lifestyle intervention reduced type 2 diabetes by 40% in men at high risk. Men with both higher endogenous T and higher PA levels have lower CV risk, but causality remains unproven. Exercise training interventions improve blood pressure and endothelial function in middle-aged and older men, without comparable benefits or additive effects of T treatment. Therefore, exercise training improves cardiometabolic health in middle-aged and older men when effectively applied as a supervised regimen incorporating aerobic and resistance modalities. Treatment with T may have indirect cardiometabolic benefits, mediated via favorable changes in body composition. Further evaluation of T as a pharmacological intervention to improve cardiometabolic health in aging men could consider longer treatment durations and combination with targeted exercise programs.

An integrative multi-modal metabolic phenotyping model was developed to assess the systemic plasma sequelae of SARS-CoV-2 (rRT-PCR positive) induced COVID-19 disease in patients with different respiratory severity levels. Plasma samples from 306 unvaccinated COVID-19 patients were collected in 2020 and classified into four levels of severity ranging from mild symptoms to severe ventilated cases. These samples were investigated using a combination of quantitative Nuclear Magnetic Resonance (NMR) spectroscopy and Mass Spectrometry (MS) platforms to give broad lipoprotein, lipidomic and amino acid, tryptophan-kynurenine pathway and biogenic amine pathway coverage. All platforms revealed highly significant differences in metabolite patterns between patients and controls (n=89) that had been collected prior to the COVID-19 pandemic. The total number of significant metabolites increased with severity with 344 out of the 1034 quantitative variables being common to all severity classes. Metabolic signatures showed a continuum of changes across the respiratory severity levels with the most significant and extensive changes being in the most severely affected patients. Even mildly affected respiratory patients showed multiple highly significant abnormal biochemical signatures reflecting serious metabolic deficiencies of the type observed in Post acute COVID -19 syndrome patients. The most severe respiratory patients had a high mortality (56.1%) and we found that we could predict mortality in this patient sub-group with high accuracy in some cases up to 61 days prior to death, based on a separate metabolic model, which highlighted a different set of metabolites to those defining the basic disease. Specifically, hexosylceramides (HCER 16:0, HCER 20:0, HCER 24:1, HCER 26:0, HCER 26:1) were markedly elevated in the non-surviving patient group (Cliff’s delta 0.91-0.95) and two phosphoethanolamines (PE.O 18:0/18:1, Cliff’s delta=-0.98 and PE.P 16:0/18:1, Cliff’s delta=-0.93) were markedly lower in the non-survivors. These results indicate that patient morbidity to mortality trajectories are determined relatively soon after infection, opening the opportunity to select more intensive therapeutic interventions to these “high risk” patients in the early disease stages.&nbsp

ObjectiveOlder men on an average have lower testosterone concentrations, compared with younger men, and more age-related comorbidities. Whether lower testosterone concentrations contribute to biological ageing remains unclear. Shorter telomeres are a marker for biological age. We tested the hypothesis that testosterone concentrations are associated with leucocyte telomere length (LTL), in middle- to older-aged men.DesignCross-sectional analysis of the UK Biobank study, involving community-dwelling men aged 40-69 years.MethodsSerum testosterone and sex hormone–binding globulin (SHBG) were assayed. Free testosterone was calculated (cFT). Leucocyte telomere length was measured using polymerase chain reaction. Multivariable models were used to assess associations of hormones with standardised LTL.ResultsIn 167 706 men, median age 58 years, adjusting for sociodemographic, lifestyle, and medical factors, total testosterone was inversely associated with standardised LTL, which was 0.09 longer (95% confidence interval [CI], 0.08-0.10, P < .001) in men with total testosterone at median of lowest quintile [Q1] vs highest [Q5]. This relationship was attenuated after additional adjustment for SHBG (0.03 longer, CI = 0.02-0.05, P = .003). The association between cFT and LTL was similar in direction but lower in magnitude. In multivariable analysis, SHBG was inversely associated with standardised LTL, which was 0.12 longer (CI = 0.10-0.13, P < .001) for SHBG at median Q1 vs Q5. Results were similar with testosterone included in the model (0.10 longer, CI = 0.08-0.12, P < .001).ConclusionsTotal testosterone and SHBG were independently and inversely associated with LTL. Men with higher testosterone or SHBG had shorter telomeres, arguing against a role for testosterone to slow biological ageing in men.

Cancer has been associated with lower risk of dementia, although methodological issues raise concerns about the validity of this association. We recruited 31,080 men aged 65–85 years who were free of cancer and dementia, and followed them for up to 22 years. We used health record linkage to identify incident cases of cancer and dementia, and split time span to investigate this association. 18,693 (60.1%) and 6897 (22.2%) participants developed cancer and dementia during follow-up. The hazard ratio (HR) of dementia associated with cancer was 1.13 (95% CI = 1.07, 1.20) and dropped to 0.85 (95% CI = 0.80, 0.91) when 449 participants who developed dementia within 2 years were excluded. The diagnosis of cancer seems to facilitate the early detection of dementia cases. Older participants who survive cancer for 2 or more years have lower risk of receiving the diagnosis of dementia over time. The factors that mediate this association remain unclear.

Guidelines advocate for intensive lipid-lowering in patients with atherosclerotic cardiovascular disease (ASCVD). In May 2020, evolocumab, a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, became government subsidised in Australia for patients with ASCVD requiring further low-density lipoprotein cholesterol (LDL-C) lowering.To identify barriers to prescribing PCSK9 inhibitors in hospitalised patients with ASCVD.A retrospective 3-month, single-site, observational analysis was conducted in consecutive patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery. Lipid-lowering therapy prescriptions, including PSCK9 inhibitors, were assessed using electronic medical records, compared against the Australian Pharmaceutical Benefits eligibility criteria, and barriers to PCSK9 inhibitor use identified.Of 331 patients, 244 (73.7%) underwent PCI and 87 (26.3%) underwent CABG surgery. A lipid profile during or within 8 weeks of admission was measured for 202 (82.8%) patients undergoing PCI and 59 (67.8%) undergoing CABG surgery. In patients taking high-intensity statins on admission (n = 109), LDL-C ≥1.4, ≥1.8 and2.6mmol/L was seen in 64 (58.7%), 44 (40.4%) and 19 (17.4%) patients respectively. High-intensity statin prescribing at discharge was high (80%); however, ezetimibe was initiated in zero patients with LDL-C ≥1.4 mmol/L. There was variable advice given by clinicians for LDL-C targets. No patients met the criteria for subsidised PSCK9 inhibitor therapy, largely due to lack of qualifying lipid levels following combined statin and ezetimibe therapy.Prescribing of non-statin LDL-C-lowering therapies remains low in patients with ASCVD. Underprescribing of ezetimibe and suboptimal lipid testing rates are barriers to accessing subsidised PCSK9i therapy using current Australian eligibility criteria.

We present a multivariate metabotyping approach to assess the functional recovery of nonhospitalized COVID-19 patients and the possible biochemical sequelae of "Post-Acute COVID-19 Syndrome", colloquially known as long-COVID. Blood samples were taken from patients ca. 3 months after acute COVID-19 infection with further assessment of symptoms at 6 months. Some 57% of the patients had one or more persistent symptoms including respiratory-related symptoms like cough, dyspnea, and rhinorrhea or other nonrespiratory symptoms including chronic fatigue, anosmia, myalgia, or joint pain. Plasma samples were quantitatively analyzed for lipoproteins, glycoproteins, amino acids, biogenic amines, and tryptophan pathway intermediates using Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry. Metabolic data for the follow-up patients (n = 27) were compared with controls (n = 41) and hospitalized severe acute respiratory syndrome SARS-CoV-2 positive patients (n = 18, with multiple time-points). Univariate and multivariate statistics revealed variable patterns of functional recovery with many patients exhibiting residual COVID-19 biomarker signatures. Several parameters were persistently perturbed, e.g., elevated taurine (p = 3.6 × 10-3 versus controls) and reduced glutamine/glutamate ratio (p = 6.95 × 10-8 versus controls), indicative of possible liver and muscle damage and a high energy demand linked to more generalized tissue repair or immune function. Some parameters showed near-complete normalization, e.g., the plasma apolipoprotein B100/A1 ratio was similar to that of healthy controls but significantly lower (p = 4.2 × 10-3) than post-acute COVID-19 patients, reflecting partial reversion of the metabolic phenotype (phenoreversion) toward the healthy metabolic state. Plasma neopterin was normalized in all follow-up patients, indicative of a reduction in the adaptive immune activity that has been previously detected in active SARS-CoV-2 infection. Other systemic inflammatory biomarkers such as GlycA and the kynurenine/tryptophan ratio remained elevated in some, but not all, patients. Correlation analysis, principal component analysis (PCA), and orthogonal-partial least-squares discriminant analysis (O-PLS-DA) showed that the follow-up patients were, as a group, metabolically distinct from controls and partially comapped with the acute-phase patients. Significant systematic metabolic differences between asymptomatic and symptomatic follow-up patients were also observed for multiple metabolites. The overall metabolic variance of the symptomatic patients was significantly greater than that of nonsymptomatic patients for multiple parameters (χ2 p = 0.014). Thus, asymptomatic follow-up patients including those with post-acute COVID-19 Syndrome displayed a spectrum of multiple persistent biochemical pathophysiology, suggesting that the metabolic phenotyping approach may be deployed for multisystem functional assessment of individual post-acute COVID-19 patients.

Context The osteoblast-derived polypeptide, osteocalcin (OC), has been associated with lower risk of type 2 diabetes and metabolic syndrome (MetS) in several epidemiological studies. Animal studies have indicated the undercarboxylated form of OC (ucOC) drives its association with metabolic outcomes. Objective We compared associations of ucOC and carboxylated OC (cOC) with MetS and its components in older men. Methods A cross-sectional analysis of 2575 men aged ≥70 years and older resident in Perth, Western Australia. ucOC was assayed using a hydroxyapatite-binding method, and cOC calculated by subtracting ucOC from total OC. Main outcome measures were MetS and its components. Results Both lower serum ucOC and cOC levels, and the proportion of cOC (%cOC) were associated with less favorable metabolic parameters (higher waist circumference, triglyceride, glucose, blood pressure, and lower high-density lipoprotein cholesterol), whereas inverse associations were found with %ucOC. Men in the lowest quintile of ucOC had higher risk of MetS compared to men in the highest quintile (Q1 ≤ 7.7 vs Q5 > 13.8 ng/mL; OR = 2.4; 95% CI, 1.8-3.2). Men in the lowest quintile of cOC had higher risk of MetS compared to those in the highest quintile (≤ 5.8 vs > 13.0 ng/mL; OR = 2.4; 95% CI, 1.8-3.2). Conclusion Lower concentrations of serum ucOC or cOC were associated with less favorable metabolic parameters and a higher risk of MetS. In contrast, a lower proportion of ucOC was associated with better metabolic parameters and lower MetS risk. Further research is warranted to determine whether ucOC and cOC are suitable biomarkers for cardiometabolic risk in men.

The endothelium is integral to the maintenance of vascular health in humans, and advancing age and low testosterone levels are associated with endothelial dysfunction in men. We compared the impacts of testosterone and exercise training, alone and in combination, on endothelium-dependent flow-mediated dilation % and endothelium-independent glyceryl trinitrate % responses. In this 2×2 factorial 12-week randomized controlled trial, 80 men aged 50 to 70 years with waist girth ≥95 cm and low-normal serum testosterone levels (6–14 nmol/L) were randomized to transdermal AndroForte5 (testosterone 5.0% w/v, 100 mg/2 mL; testosterone), or matching placebo; and to supervised centre-based exercise or no additional exercise. Testosterone increased serum testosterone levels (testosterone×time, P =0.003) to the extent that 62% of subjects in testosterone groups increased levels to >14 nmol/L, whereas placebo treatment had no impact on testosterone levels. Exercise training increased flow-mediated dilation % (exercise×time, P =0.033; testosterone+exercise: +0.5, placebo+exercise: +1.0 versus testosterone+no additional exercise: −0.7, placebo+no additional exercise: +0.2%), whereas testosterone did not impact flow-mediated dilation, nor was it additive to exercise (all P >0.05). There were no significant exercise or drug main effects on glyceryl trinitrate responses (all P >0.05). Exercise training improved endothelium-dependent vasodilator function, whereas administration of testosterone at therapeutic doses did not impact flow-mediated dilation % or add to the exercise benefit. Vascular smooth muscle sensitivity to nitric oxide was not modified by exercise, testosterone, or their combination. In middle-to-older-aged men with central adiposity and low/normal testosterone levels, we observed no evidence that testosterone added to the beneficial impact of exercise on vascular function and health. REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368611 ; Unique identifier: ACTRN12615000600549.