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).

Cancer care partners' behavioral intention to use autonomy enhancing communication skills during accompanied visits after online skill training.

OBJECTIVE: The study objective is to evaluate an adaptation of the LEAPS skill framework for cancer care partners (CPs) focusing on autonomy enhancing skills and assessed by strong behavioral intention (SBI) to use these skills METHOD: Cancer CPs were recruited through public platforms to view and rate 4 LEAPS cancer-specific narratives and 52 skill demonstration videos, indicate SBI to use demonstrated skills and provide information on skill-related measures. RESULTS: Half of CPs expressed SBI to use an average of 6.5 of 13 LEAPS skills which did not vary by LEAPS communication domains or examples used to demonstrate skills. Significant predictors of SBI include positive ratings of program narratives and past use of LEAPS-related behaviors in the communication domain of shared decision making (SDM). CONCLUSION: CPs indicated SBIs to use multiple autonomy enhancing skills and positively rated program videos after exposure to the brief LEAPS training program. PRACTICE IMPLICATIONS: The brevity of the LEAPS training videos make it possible for users to view an individual cancer-specific narrative and 13 skill demonstrations in roughly 6 min. This ultra-brief training can benefit care partners and the patients they accompany by increasing the likelihood that autonomy enhancing skills are used during accompanied visits.

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).

Leflutrozole in male obesity-associated hypogonadotropic hypogonadism: Ph 2b double-blind randomised controlled trial.

OBJECTIVE: Assessment of the efficacy and safety/tolerability of the aromatase inhibitor leflutrozole to normalise testosterone in Obesity-associated Hypogonadotropic Hypogonadism (OHH). DESIGN: Placebo-controlled, double-blind, RCT, in 70 sites in Europe/USA. METHODS: Patient inclusion criteria: men with BMI of 30-50 kg/m2, morning total testosterone (TT) < 10.41 nmol/L, and two androgen deficiency symptoms (at least one of sexual dysfunction). Patients randomised to weekly leflutrozole (0.1/0.3/1.0 mg) or placebo for 24 weeks. Primary endpoint: normalisation of TT levels in ≥75% of patients after 24 weeks. Secondary endpoints (included): time to TT normalisation and change in LH/FSH. Safety was assessed through adverse events and laboratory monitoring. RESULTS AND CONCLUSIONS: Of 2103 screened, 271 were randomised, 81 discontinued. Demographic characteristics were similar across groups. Mean BMI was 38.1 kg/m2 and TT 7.97 nmol/L. The primary endpoint was achieved in all leflutrozole-treated groups by 24 weeks with a dose-tiered response; mean TT 15.89; 17.78; 20.35 nmol/L, for leflutrozole 0.1 mg, 0.3 mg, and 1.0 mg groups respectively, vs 8.04 nmol/L for placebo. LH/FSH significantly increased in leflutrozole vs placebo groups. No improvements in body composition or sexual dysfunction were observed. Semen volume/total motile sperm count improved with leflutrozole vs placebo. Treatment-emergent adverse events, more common in leflutrozole-treated groups included, raised haematocrit, hypertension, increased PSA, and headache. Some reduction in lumbar bone density was observed with leflutrozole (mean -1.24%, -1.30%, -2.09%) and 0.66% for 0.1 mg, 0.3 mg, 1.0 mg, and placebo, respectively, without change at the hip. This RCT of leflutrozole in OHH demonstrated normalisation of TT in obese men. FSH/LH and semen parameter changes support that leflutrozole may preserve/improve testicular function. CLINICAL TRIAL REGISTRATION NUMBER: NCT02730169.

Improving cancer care for underserved populations in an academic and community practice setting: protocol for a community health worker pilot navigation programme.

INTRODUCTION: Delaying cancer treatment following diagnosis impacts health outcomes, including increasing patient distress and odds of mortality. Interventions to promote timely healthcare engagement may decrease patient-reported stress and improve quality of life. Community health workers (CHWs) represent an enabling resource for reducing delays in attending initial oncology treatment visits. As part of an ongoing programme evaluation coordinated by the Merck Foundation, we will implement a pilot navigation programme comprising CHW-conducted needs assessments for supporting patients and their caregivers. We aim to investigate (1) the programme's influence on patients' healthcare utilisation within the period between their first diagnosis and initial treatment visit and (2) the logistic feasibility and acceptability of programme implementation. METHODS AND ANALYSIS: We will employ a hybrid implementation design to introduce the CHW navigation programme at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. CHW team members will use a consecutive sampling approach. Participants will complete the Problem-Checklist, Chronic Illness Distress Scale and the Satisfaction with Life Domains instruments. CHWs will provide tailored guidance by sharing information available on the Johns Hopkins Electronic Resource databases. The investigators will evaluate patients' time to initial oncology treatment and healthcare utilisation by reviewing electronic medical records at 3 and 6 months postintervention. Bivariate analyses will be completed to evaluate the relationships between receiving the programme and all outcome measures. ETHICS AND DISSEMINATION: This study's protocol was approved by the Johns Hopkins School of Medicine's institutional review board (IRB00160610). Informed consent will be obtained by phone by the CHW navigator. Dissemination planning is ongoing through regular meetings between members of the investigator team and public members of two community advisory groups. Study plans include collaborating with other experts from the Johns Hopkins Institute for Clinical and Translational Research and the Johns Hopkins Center for Health Equity for ideating dissemination strategies.

Testosterone Treatment and the Risk of Prostate Adverse Events.

Hypogonadism is a common clinical condition affecting men, with older men having an increased incidence. Clinicians (endocrinologists and urologists) who may be involved in providing testosterone therapy should be familiar with the effects of testosterone on the prostate. Before initiating testosterone therapy, physicians and patients should partake in shared decision-making, including pretreatment testing, risks and benefits of testosterone therapy relating to benign prostatic hyperplasia and lower urinary tract symptoms, a discussion on prostate cancer in those who have not been diagnosed with malignancy, and a thorough discussion with patients who may have a previous diagnosis of prostate cancer.

Amplifying Their Voices: Advice, Guidance, and Perceived Value of Cancer Biobanking Research Among an Older, Diverse Cohort.

The use of biobanks may accelerate scientists' chances of developing cures and treatments that are tailored to individuals' biological makeup-a function of the precision medicine movement. However, given the underrepresentation of certain populations in biobanks, the benefits of these resources may not be equitable for all groups, including older, multi-ethnic populations. The objective of this study was to better understand older, multi-ethnic populations' (1) perceptions of the value of cancer biobanking research, (2) study design preferences, and (3) guidance on ways to promote and increase participation. This study was designed using a community-based participatory research (CBPR) approach and involved eight FGDs with 67 older (65-74 years old) black and white residents from Baltimore City and Prince George's County, MD. FGDs lasted between 90 and 120 min, and participants received a $25 Target gift card for their participation. Analysis involved an inductive approach in which we went through a series of open and axial coding techniques to generate themes and subthemes. Multiple themes emerged from the FGDs for the development of future cancer-related biobanking research including (1) expectations/anticipated benefits, (2) biobanking design preferences, and (3) ways to optimize participation. Overall, most participants were willing to provide biospecimens and favored cancer-related biobank. To increase participation of older, diverse participants in biobanking protocols, researchers need to engage older, diverse persons as consultants in order to better understand the value of biobanking research to individuals from the various populations. Scientists should also incorporate suggestions from the community on garnering trust and increasing comfort with study design.

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

CONTEXT: Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase. OBJECTIVE: To analyze associations of baseline serum testosterone and SHBG concentrations, and calculated free testosterone (cFT) values, with all-cause and cause-specific mortality in men. DESIGN, SETTING, AND PARTICIPANTS: The UK Biobank prospective cohort study of community-dwelling men aged 40-69 years old, followed for 11 years. MAIN OUTCOME MEASURES: All-cause, atherosclerotic cardiovascular disease (CVD) and cancer-related mortality. Cox proportional hazards regression was performed, adjusting for age, waist circumference, medical conditions, and other covariates. Models for testosterone included SHBG and vice versa. RESULTS: In a complete case analysis of 149 436 men with 10 053 deaths (1925 CVD and 4927 cancer-related), men with lower testosterone had a higher mortality rate from any cause (lowest vs highest quintile, Q1 vs Q5, fully-adjusted hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 1.06-1.22, overall trend P < 0.001), and cancer (HR = 1.20, CI = 1.09-1.33, P < 0.001), with no association for CVD deaths. Similar results were seen for cFT. Men with lower SHBG had a lower mortality rate from any cause (Q1 vs Q5, HR = 0.68, CI = 0.63-0.73, P < 0.001), CVD (HR = 0.70, CI = 0.59-0.83, P < 0.001), and cancer (HR = 0.80, CI = 0.72-0.89, P < 0.001). A multiply imputed dataset (N = 208 425, 15 914 deaths, 3128 CVD-related and 7468 cancer-related) and analysis excluding deaths within the first 2 years (9261, 1734, and 4534 events) yielded similar results. CONCLUSIONS: Lower serum testosterone is independently associated with higher all-cause and cancer-related, but not CVD-related, mortality in middle-aged to older men. Lower SHBG is independently associated with lower all-cause, CVD-related, and cancer-related mortality. Confirmation and determination of causality requires mechanistic studies and prospective trials.

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

INTRODUCTION: This study aims to clarify the role(s) of endogenous sex hormones to influence health outcomes in men, specifically to define the associations of plasma testosterone with incidence of cardiovascular events, cancer, dementia and mortality risk, and to identify factors predicting testosterone concentrations. Data will be accrued from at least three Australian, two European and four North American population-based cohorts involving approximately 20 000 men. METHODS AND ANALYSIS: Eligible studies include prospective cohort studies with baseline testosterone concentrations measured using mass spectrometry and 5 years of follow-up data on incident cardiovascular events, mortality, cancer diagnoses or deaths, new-onset dementia or decline in cognitive function recorded. Data for men, who were not taking androgens or drugs suppressing testosterone production, metabolism or action; and had no prior orchidectomy, are eligible. Systematic literature searches were conducted from 14 June 2019 to 31 December 2019, with no date range set for searches. Aggregate level data will be sought where individual participant data (IPD) are not available. One-stage IPD random-effects meta-analyses will be performed, using linear mixed models, generalised linear mixed models and either stratified or frailty-augmented Cox regression models. Heterogeneity in estimates from different studies will be quantified and bias investigated using funnel plots. Effect size estimates will be presented in forest plots and non-negligible heterogeneity and bias investigated using subgroup or meta-regression analyses. ETHICS AND DISSEMINATION: Ethics approvals obtained for each of the participating cohorts state that participants have consented to have their data collected and used for research purposes. The Androgens In Men Study has been assessed as exempt from ethics review by the Human Ethics office at the University of Western Australia (file reference number RA/4/20/5014). Each of the component studies had obtained ethics approvals; please refer to respective component studies for details. Research findings will be disseminated to the scientific and broader community via the publication of four research articles, with each involving a separate set of IPD meta-analyses (articles will investigate different, distinct outcomes), at scientific conferences and meetings of relevant professional societies. Collaborating cohort studies will disseminate findings to study participants and local communities. PROSPERO REGISTRATION NUMBER: CRD42019139668.

Male reproductive health in cystic fibrosis.

The impact of cystic fibrosis (CF) on male reproductive health is profound. The vast majority of men with CF are infertile due to obstructive azoospermia. Multiple factors associated with CF contribute to an increased prevalence of testosterone deficiency, which adversely affects muscle mass, bone density, and quality of life. This article reviews the pathophysiology, diagnosis, and management of infertility and testosterone deficiency that occur in men with CF. With improving survival of CF patients, these topics are becoming more significant in their clinical care.

Nationally Representative Estimates of Serum Testosterone Concentration in Never-Smoking, Lean Men Without Aging-Associated Comorbidities.

CONTEXT: Testosterone deficiency prevalence increases with age, comorbidities, and obesity. OBJECTIVE: To inform clinical guidelines for testosterone deficiency management and development of targets for nonpharmacologic intervention trials for these men, we determined serum testosterone in never-smoking, lean men without select comorbidities in nationally representative surveys. DESIGN SETTING PARTICIPANTS: We used cross-sectional data for never-smoking, lean men ≥20 years without diabetes, myocardial infarction, congestive heart failure, stroke, or cancer, without use of hormone-influencing medications, and participated in morning sessions of National Health and Nutrition Examination Survey (NHANES) III (phase I 1988-1991) or continuous NHANES (1999-2004). By age, we determined median total testosterone (ng/mL) measured previously by a Food and Drug Administration-approved immunoassay and median estimated free testosterone concentration. RESULTS: In NHANES III, in never-smoking, lean men without comorbidities, median (25th, 75th percentile) testosterone was 4% to 9% higher than all men-20 to 39 years: 6.24 (5.16, 7.51), 40 to 59: 5.37 (3.83, 6.49), and ≥60: 4.61 (4.01, 5.18). In continuous NHANES, in never-smoking, lean men without comorbidities, levels were 13% to 24% higher than all men-20 to 39 years: 6.26 (5.32, 7.27), 40 to 59: 5.86 (4.91, 6.55), and ≥60: 4.22 (3.74, 5.73). In never-smoking, lean men without comorbidities, median estimated free testosterone was similar to (NHANES III) or slightly higher than (continuous NHANES) in all men. CONCLUSIONS: These nationally representative data document testosterone levels (immunoassay) in never-smoking, lean men without select comorbidities 30 and 15 to 20 years ago. This information can be incorporated into guidelines for testosterone deficiency management and used to develop targets for nonpharmacologic intervention trials for testosterone deficiency.

Age-Specific Serum Total and Free Estradiol Concentrations in Healthy Men in US Nationally Representative Samples.

PURPOSE: To report age-specific serum estradiol concentration in nonsmoking, lean US men without comorbidities. We provide concentrations from 30 and 15 to 20 years ago given previously described declines in serum estradiol in US men over time. METHODS: We used data from the Third National Health and Nutrition Examination Survey (NHANES III; 1988 to 1991) and continuous NHANES (1999 to 2004). Serum estradiol and SHBG were previously measured by competitive electrochemiluminescence immunoassays. Free estradiol was estimated from estradiol, SHBG, and albumin. By age, we calculated median concentrations overall and for nonsmoking, lean (body mass index <25 kg/m2 and waist <102 cm) men without diabetes, cardiovascular disease, or cancer. RESULTS: Overall, respective total estradiol medians for men ages 20 to 39, 40 to 59, and ≥60 years old were 37.0, 33.9, and 33.5 pg/mL in NHANES III and 31.3, 30.5, and 27.0 pg/mL in continuous NHANES. In nonsmoking, lean men without comorbidities, respective total estradiol medians were 32.0, 32.1, and 32.0 pg/mL in NHANES III and 29.1, 22.7, and 26.1 pg/mL in continuous NHANES. Overall, respective free estradiol medians were 0.82, 0.72, and 0.64 pg/mL in NHANES III and 0.67, 0.61, and 0.47 pg/mL in continuous NHANES. In nonsmoking, lean men without comorbidities, respective free estradiol medians were 0.64, 0.67, and 0.62 pg/mL in NHANES III and 0.58, 0.42, and 0.40 pg/mL continuous NHANES. CONCLUSION: We report US nationally representative serum estradiol concentrations in healthy men, which could be used for targeting estradiol during testosterone supplementation and for general good health.

Association Between Statin Use and Sex Hormone in the Multi-Ethnic Study of Atherosclerosis Cohort.

PURPOSE: Based on the 2018 American College of Cardiology/American Heart Association cholesterol guidelines, the number of individuals eligible for statin therapy to reduce atherosclerotic cardiovascular disease risk has greatly expanded. Statins inhibit cholesterol biosynthesis, which can impair gonadal steroidogenesis. We evaluated the effect of statins on endogenous sex hormones in a large epidemiological study. METHODS: A total of 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants underwent the baseline examination. Of these, 6171 had measurements of serum sex hormones available: dehydroepiandrosterone (DHEA), SHBG, estradiol, and total and bioavailable testosterone. Multivariable linear regression models were used to assess the relationship of statin use with each sex hormone. RESULTS: A total of 345 women (17.4%) and 464 men (14.7%) were statin users (mean age, 67 years; 41% white, 29% black, 11% Chinese, and 19% Hispanic). Among the users vs nonusers of statins, the mean SHBG was 3.54 nmol/L (P < 0.01) lower in women and 3.37 nmol/L (P < 0.001) lower in men; the mean DHEA was 1.06 nmol/L (P < 0.05) lower in women and 0.70 nmol/L (P < 0.01) lower in men, after adjustment for potential confounders. With further propensity score adjustment, the mean DHEA and SHBG levels were 0.67 nmol/L (P < 0.05) and 3.49 nmol/L (P < 0.001) lower, respectively, for statin users vs nonusers. No statistically significant association was noted between estradiol, total testosterone, and bioavailable testosterone and statin use. CONCLUSION: Statin users have lower levels of SHBG and DHEA. This is especially relevant owing to the increasing use of statin therapy.

Consumption of caffeinated beverages and serum concentrations of sex steroid hormones in US men.

BACKGROUND: By modulating the levels of sex steroid hormones and sex hormone-binding globulin (SHBG), caffeine could be a factor in the development of several conditions in men, including prostate cancer. The aim of this study was to evaluate if caffeine consumption is associated with concentrations of sex steroid hormones and SHBG in men. METHODS: 1,410 men aged 20 + years who attended the morning examination session of the Third National Health and Nutrition Examination Survey (1988-1991) were included in the analysis. Coffee and soft drink consumption was assessed using a food frequency questionnaire. Daily caffeine intake was estimated by multiplying caffeine content per cup times the daily frequency of coffee, tea, or soft drink consumption. Serum levels of hormones and SHBG were measured by immunoassay. Associations of frequency of beverage consumption or estimated caffeine intake with hormone levels were examined using multivariable linear regression. RESULTS: Coffee consumption was positively associated with SHBG concentration (p = 0.045) taking lifestyle factors into account, but mutually adjusting for testosterone and estradiol attenuated the association; no association with SHBG was observed for soft drink consumption or caffeine intake. No associations between caffeinated beverage consumption and androgen or estrogen concentrations were observed. CONCLUSION: Men who drink coffee more frequently may have higher circulating SHBG concentration, but there were no consistent associations for soft drinks or caffeine intake.

Inflammation, Immune Activation, Immunosenescence, and Hormonal Biomarkers in the Frailty-Related Phenotype of Men With or at Risk for HIV Infection.

Background: The extent to which inflammation, immune activation/immunosenescence, and hormonal abnormalities are driven by human immunodeficiency virus (HIV) or frailty is not clear. Methods: HIV-infected frail men (n = 155) were matched to nonfrail, HIV-infected (n = 141) and HIV-uninfected (n = 150) men by age, calendar year, and antiretroviral therapy use (HIV-infected men only). Frailty was defined by ≥3 frailty-related phenotype criteria (weight loss, exhaustion, low activity, slowness) at ≥2 visits, or at 1 visit with ≥1 criteria at ≥2 visits. The following measurements were obtained: interleukin 6, high-sensitivity C-reactive protein, soluble receptors for tumor necrosis factor α 1 and 2, the percentages of CD4+CD28-, CD8+CD28-, CD4+CD38+HLA-DR+, and CD8+CD38+HLA-DR+ T cells, dehydroepiandrosterone sulfate, free testosterone, homeostatic model assessment of insulin resistance, and insulin-like growth factor 1. Log-linear regressions were adjusted for a priori selected covariates to determine differences by frailty and HIV status. Results: In multivariate analyses adjusted for covariates, frailty was associated among HIV-infected men with higher interleukin 6 and high-sensitivity C-reactive protein and lower free testosterone and dehydroepiandrosterone levels. In contrast, HIV infection but not frailty was associated with significantly greater immune senescence (percentage of CD4+CD28- or CD8+CD28- T cells) and immune activation (percentages of CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ T cells). Conclusions: Frailty among HIV-infected men was associated with increased inflammation and lower hormone levels, independent of comorbid conditions. Interventions targeting these pathways should be evaluated to determine the impact on prevention or reversal of frailty among HIV-infected men.

Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions.

To address widespread concerns regarding the medical condition of testosterone (T) deficiency (TD) (male hypogonadism) and its treatment with T therapy, an international expert consensus conference was convened in Prague, Czech Republic, on October 1, 2015. Experts included a broad range of medical specialties including urology, endocrinology, diabetology, internal medicine, and basic science research. A representative from the European Medicines Agency participated in a nonvoting capacity. Nine resolutions were debated, with unanimous approval: (1) TD is a well-established, clinically significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life; (2) symptoms and signs of TD occur as a result of low levels of T and may benefit from treatment regardless of whether there is an identified underlying etiology; (3) TD is a global public health concern; (4) T therapy for men with TD is effective, rational, and evidence based; (5) there is no T concentration threshold that reliably distinguishes those who will respond to treatment from those who will not; (6) there is no scientific basis for any age-specific recommendations against the use of T therapy in men; (7) the evidence does not support increased risks of cardiovascular events with T therapy; (8) the evidence does not support increased risk of prostate cancer with T therapy; and (9) the evidence supports a major research initiative to explore possible benefits of T therapy for cardiometabolic disease, including diabetes. These resolutions may be considered points of agreement by a broad range of experts based on the best available scientific evidence.

Mobilizing social support networks to improve cancer screening: the COACH randomized controlled trial study design.

BACKGROUND: Disadvantaged populations face many barriers to cancer care, including limited support in navigating through the complexities of the healthcare system. Family members play an integral role in caring for patients and provide valuable care coordination; however, the effect of family navigators on adherence to cancer screening has not previously been evaluated. Training and evaluating trusted family members and other support persons may improve cancer outcomes for vulnerable patients. METHODS: Guided by principles of community based participatory research (CBPR), "Evaluating Coaches of Older Adults for Cancer Care and Healthy Behaviors (COACH)" is a community-based randomized controlled trial to assess the effectiveness of a trained participant-designated coach (support person or care giver) in navigating cancer-screening for older African American adults, 50-74 years old. Participants are randomly assigned as dyads (participant+coach pair) to receiving either printed educational materials only (PEM--control group) or educational materials plus coach training (COACH--intervention group). We defined a coach as family member, friend, or other lay support person designated by the older adult. The coach training is designed as a one-time, 35- to 40-minute training consisting of: 1) a didactic session that covers the role of the coach, basic facts about colorectal, breast and cervical cancers (including risk factors, signs and symptoms and screening modalities), engaging the healthcare provider in cancer screening, insurance coverage for screening, and related healthcare issues, 2) three video skits addressing misconceptions about and planning for cancer screening, and 3) an interactive role-play session with the trainer to reinforce and practice strategies for encouraging the participant to get screened. The primary study outcome is the difference in the proportion of participants completing at least one of the recommended screenings (for breast, cervix or colorectal cancer) between the control and intervention groups. DISCUSSION: Building on trusted patient contacts to encourage cancer screening, COACH is a highly sustainable intervention in a high-risk population. It has the potential to minimize the effect of mistrust of the medical establishment on screening behaviors by mobilizing participants' existing support networks. If effective, the intervention could have a high impact on health care disparities research across multiple diseases. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01613430 ). Registered June 5, 2012.

Osteoprotegerin, but Not Receptor Activator for Nuclear Factor-κB Ligand, is Associated With Subclinical Coronary Atherosclerosis in HIV-Infected Men.

CONTEXT: Abnormalities in the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) axis have been observed in HIV-infected persons and have been implicated in cardiovascular disease (CVD) pathogenesis in the general population. OBJECTIVE: To determine associations of serum OPG and RANKL concentrations with HIV infection and subclinical atherosclerosis. DESIGN: Cross-sectional study nested within the Multicenter AIDS Cohort Study. SETTING: Four US academic medical centers. PARTICIPANTS: There were 578 HIV-infected and 344 HIV-uninfected men. MAIN OUTCOME MEASURES: Coronary artery calcium (CAC) was measured by noncontrast cardiac computed tomography, and coronary stenosis and plaque characteristics (composition, presence, and extent) were measured by coronary computed tomography angiography. All statistical models were adjusted for traditional CVD risk factors. RESULTS: OPG concentrations were higher, and RANKL concentrations were lower among HIV-infected men compared with HIV-uninfected men (P < 0.0001 each). Among HIV-infected men, higher OPG concentrations were associated with the presence of CAC, mixed plaque, and coronary stenosis >50%, but not with plaque extent. In contrast, among HIV-uninfected men, higher OPG concentrations were associated with the extent of both CAC and calcified plaque, but not with their presence. RANKL concentrations were not associated with plaque presence or the extent among HIV-infected men, but among HIV-uninfected men, lower RANKL concentrations were associated with greater extent of CAC and total plaque. CONCLUSIONS: OPG and RANKL are dysregulated in HIV-infected men, and their relationship to the presence and extent of subclinical atherosclerosis varies by HIV status. The role of these biomarkers in CVD pathogenesis and risk prediction may be different in HIV-infected men.

Circulating total testosterone and PSA concentrations in a nationally representative sample of men without a diagnosis of prostate cancer.

BACKGROUND: The association between serum sex steroid hormones and PSA in a general population has not been described. METHODS: Included were 378 men aged 40-85 years who participated in the National Health and Nutrition Examination Survey in 2001-2004, who did not have a prostate cancer diagnosis, and had not had a recent biopsy, rectal examination, cystoscopy, or prostate infection or inflammation. Serum total PSA, total testosterone, androstanediol glucuronide (3α-diol-G), estradiol, and sex hormone binding globulin (SHBG) concentrations were previously measured. Free testosterone was estimated by mass action. We applied sampling weights and calculated geometric mean PSA concentration by hormone quintiles adjusting for age and race/ethnicity, and also for body mass index, waist circumference, smoking, diabetes, and mutually for hormones. We estimated the OR of PSA ≥2.5 ng/ml per hormone quintile using logistic regression. RESULTS: Geometric mean PSA increased across testosterone quintiles after age and race/ethnicity (Q1: 0.80, Q5: 1.14 ng/ml; P-trend = 0.002) and multivariable (Q1: 0.79, Q5: 1.16 ng/ml; P-trend = 0.02) adjustment; patterns were similar for free testosterone and 3α-diol-G. SHBG was inversely associated with PSA only after multivariable adjustment (Q1: 1.32, Q5: 0.82 nmol/L; P-trend = 0.01). Estradiol and PSA were not associated. The OR of PSA ≥2.5 ng/ml was 1.54 (95% CI 1.18-2.01) per testosterone quintile after age and race/ethnicity adjustment, and 1.78 (95% CI 1.16-2.73) after multivariable adjustment. CONCLUSIONS: In this nationally representative sample, men with higher testosterone had higher PSA even after taking into account other hormones and modifiable factors. Men with higher SHBG had lower PSA, but only after multivariable adjustment.

Lipodystrophy and inflammation predict later grip strength in HIV-infected men: the MACS Body Composition substudy.

Body fat changes in HIV-infected persons are associated with increased systemic inflammation and increased mortality. It is unknown whether lipodystrophy is also associated with declines in physical function. Between 2001 and 2003, 33 HIV-infected men with evidence of lipodystrophy (LIPO⁺), 23 HIV-infected men without lipodystrophy (LIPO⁻), and 33 seronegative men were recruited from the Multicenter AIDS Cohort Study (MACS) for the Body Composition substudy. Visceral adipose tissue (VAT) was assessed by quantitative computed tomography. Lean body mass (LBM) and extremity fat were measured by dual-energy x-ray absorptiometry. Insulin resistance was estimated by Homeostatic Model Assessment (HOMA). Serum interleukin (IL)-6, soluble tumor necrosis factor (TNF)-α receptors I and II (sTNFRI and sTNFRII), and highly sensitive C-reactive protein (hs-CRP) concentrations were quantified from archived serum samples. These measurements were correlated with grip strength measured in 2007 using linear regression. At the substudy visit, the LIPO⁺ group had higher HOMA, sTNFRI, sTNFRII, and IL-6 levels than the LIPO⁻ group. In 2007, the LIPO⁺ group had lower median grip strength than the LIPO⁻ group (34.4 vs. 42.7 kg, p=0.002). Multivariable analysis of HIV⁺ men showed older age, lower LBM, higher sTNFRII concentrations, and LIPO⁺ status [adjusted mean difference -4.9 kg (p=0.045)] at the substudy visit were independently associated with lower subsequent grip strength. Inflammation, lower LBM, and lipodystrophy in HIV-infected men were associated with lower subsequent grip strength. These findings suggest that inflammation may contribute to declines in functional performance, independent of age.