Effects of testosterone-augmented multimodal exercise intervention in spinal cord injury: a randomized controlled trial

The Journal of Clinical Endocrinology & Metabolism · 2026-04-15

CONTEXT: Spinal cord injury (SCI) leads to profound muscle atrophy, aerobic deconditioning, and metabolic dysfunction. Exercise-based interventions alone produce modest benefits. Whether testosterone can augment physiologic responses to exercise in this population remains untested. OBJECTIVE: To evaluate efficacy and safety of home-based intervention combining functional electrical stimulation-assisted leg cycling (FES-LC), arm ergometry (AE) and testosterone compared with FES-LC, AE plus placebo in adults with SCI. METHODS: This randomized, placebo-controlled, double-blind trial enrolled 84 adults (76 males and 8 females) aged 19-70 years with SCI (neurologic levels C4-T12; AIS grades A-D). Participants were randomized to multimodality intervention (home-based FES-LC, AE and intramuscular testosterone undecanoate) (n=38) or control intervention (FES-LC, AE plus placebo) (n=46) for 16 weeks. The primary outcome was change in aerobic capacity (peak VO2) during AE cardiopulmonary exercise testing. Secondary outcomes included lean mass, hemoglobin, cardiometabolic markers and safety. RESULTS: Mean (SD) age was 44 (13) yrs and time since injury was 13.9 (13) years). Between-group changes in peak VO2 were not statistically significant. Within-group improvements were larger in multimodality (∼19% increase; 0.10 L/min; 95% CI, 0.02-0.18 L/min) compared to controls (∼6% increase; 0.06 L/min; 95% CI, -0.01-0.13). The multimodality group gained significantly more lean mass (whole-body:1.84 kg, 95% CI: 0.52-3.16, P =.007; lower extremity 0.92 kg, 95% CI: 0.38-1.45, P =.001), and anemia was corrected in a greater proportion of participants. Adverse event rates were similar between groups. CONCLUSIONS: A home-based multimodality intervention combining FES-LC, AE, and testosterone was safe and associated with greater improvements in lean mass and hemoglobin. Although between-group differences in aerobic capacity were not statistically significant, greater within-group increases were observed in the multimodality group. These findings may inform future studies of testosterone-augmented exercise interventions for individuals living with SCI.

Activated GDF11/8 subforms predict cardiovascular events and mortality in humans

Nature Communications · 2025-07-15 · 1 citations

Circulating Growth Differentiation Factors 11 and 8 (GDF11/8) exist in both latent and active forms, and it is unclear if specific forms can predict disease outcomes. Our data suggest that a dual-specific aptamer selectively binds GDF11/8 after prodomain activation. In 11,609 patients at risk for future cardiovascular events, low dual-specific aptamer-detected GDF11/8 levels strongly predicted adverse outcomes, including cardiovascular events (HR = 0.43, p = 9.1 × 10⁻⁶³) and all-cause mortality (HR = 0.33, p = 4.8 × 10⁻⁴⁰). Use of selective aptamers suggested that results observed with the dual-specific aptamer for cardiovascular and mortality risk replicated with a GDF8 aptamer although with a smaller effect size. In a second cohort of 4110 individuals (ARIC), low dual-specific aptamer-detected GDF11/8 levels also predicted increased 8 year dementia risk (HR = 0.66, p = 0.00148). Our findings reveal that activation of GDF11/8 may be a factor in future aging-related cardiovascular and cognitive decline. The predictive value of blood levels of GDF11/8 proteins in humans for future disease outcomes has been unclear. Here, the authors show that low levels of specific activated GDF11/8 subforms are strongly associated with future cardiovascular events, mortality, and dementia risk.

The association between reproductive factors and neurocognitive and neuroimaging markers of brain aging

Journal of Alzheimer s Disease · 2025-09-09

BackgroundWomen have a higher risk of dementia than men. Reproductive factors may be implicated.ObjectiveDetermine the association between reproductive factors (earlier menarche, later menopause, longer reproductive lifespan (RLS), post-menopausal hormone replacement therapy [pmHRT] use, and serum estradiol/estrone) and neurocognitive and neuroimaging markers of brain aging and incident dementia in cognitively healthy women.MethodsLifetime reproductive factors were measured in dementia-free women [mean age 60.3 (SD 9.3) year] from the Framingham Heart Study Offspring cohort between 1998-2001 and related to concurrent neurocognitive (n = 1329) and MRI brain measures (n = 1165) using multivariable linear regression and risk of incident dementia (secondary outcome, n = 921) using Cox proportional hazards regression.ResultsUse of pmHRT (Beta (β, standardized regression coefficient)±standard error (SE), 0.14 ± 0.05, p = 0.009), elevated serum estradiol (0.06 ± 0.03, p = 0.02) and earlier menarche (≥14 years versus 12-13 years, -0.13 ± 0.06, p = 0.03) were associated with better abstract reasoning (Similarities). Older age at menopause (≥52 years versus the referent 50-51 years) (0.18 ± 0.09, p = 0.04), elevated serum estradiol (0.06 ± 0.03, p = 0.02), and 1-2 (0.17 ± 0.08, p = 0.03) or ≥3 (0.22 ± 0.08, p = 0.007) versus no live births were associated with superior visuospatial performance (Hooper's visual organization test). Earlier menopause age was associated with lower hippocampal volume (≤49 years versus 50-51 years, -0.11 ± 0.04, p = 0.02) while 1-2 (5.50 ± 1.95, p = 0.005) and ≥3 live births (β±SE, 4.94 ± 1.96, p = 0.01) were associated with greater total cerebral brain volume.ConclusionsIn general, greater exposure to estrogen throughout a woman's reproductive lifespan was associated with enhanced cognitive performance and larger brain volumes. Our results may suggest positive cognitive benefits of greater lifetime estrogen exposure, but require further validation.

Selecting Appropriate Clinical Trial Endpoints for Geroscience Trials: A Path Towards Consensus

Research Square · 2025-02-12 · 2 citations

Oral <scp>MIB</scp> ‐626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in Hospitalized Patients With <scp>COVID</scp> ‐19 and Acute Kidney Injury: A Randomized Controlled Trial

FASEB BioAdvances · 2025-06-18

ABSTRACT Nicotinamide adenine dinucleotide (NAD + ) plays an important role in the innate immune response and is depleted during SARS‐CoV‐2 infection due to increased turnover. It is unknown whether treatment with NAD + precursors can safely raise NAD + levels in patients with COVID‐19. To determine whether MIB‐626 ( β‐ nicotinamide mononucleotide), an NAD + precursor, can safely increase blood NAD + levels and attenuate acute kidney injury (AKI) and inflammation in hospitalized patients with COVID‐19, 42 adults, ≥ 18 years, hospitalized with COVID‐19 and AKI, were randomized in a 3:2 ratio to MIB‐626 1.0‐g or placebo tablets twice daily for 14 days. Circulating NAD + and its metabolites, markers of AKI, inflammation, and disease severity, were assessed. MIB‐626 treatment significantly but gradually raised blood NAD + levels to a peak between 5 to 14 days (16.0 ± 6.9, 25.5 ± 12.6, and 42.6 ± 25.6 μg/mL at baseline, days 5 and 14) and raised plasma concentrations of NAD + metabolites 1‐methylnicotinamide, N‐methyl, 2‐pyridone, 4‐carboxamide rapidly to a peak by day 3. Changes in serum creatinine, cystatin‐C, and serum markers of AKI did not differ significantly between groups. Serum CRP, IL‐6, and TNFα and indices of disease severity also did not differ between groups. MIB‐626 treatment of patients with COVID‐19 and AKI safely and substantially raised blood NAD + and plasma concentrations of NAD + metabolites. Markers of AKI, inflammation, and disease severity did not differ between groups, likely due to the slow rise in NAD + levels. Future studies should assess whether a rapid increase in NAD + by parenteral administration can attenuate disease severity and AKI. Trial Registration: ClinicalTrials.gov Identifier: NCT05038488

Testosterone and Cardiovascular Disease

2025-01-01

Longitudinal Changes in Sex Hormones in a Population of Older Community-dwelling Men

The Journal of Clinical Endocrinology & Metabolism · 2025-12-11 · 1 citations

CONTEXT: Based on cross-sectional studies and short longitudinal studies, levels of sex hormones (SHs) change with age in men. However, there are limited data about SHs in men older than age 80 years and few longitudinal studies >10 years. OBJECTIVE: The aim of this study was to characterize SH concentrations in older men and assess long-term changes. METHODS: We studied 477 community-dwelling men, ages 78 to 97 years, who participated in the Osteoporotic Fractures in Men study. Medical history was obtained via clinical visits and questionnaires. Serum sex steroid levels (testosterone, estradiol, estrogen, DHT) were assayed using liquid chromatography/mass spectrometry, free testosterone by equilibrium dialysis, and sex hormone binding globulin (SHBG) by radioimmunoassay. In 215 men, SH levels were compared to levels obtained 14.0 ± 0.65 years earlier. RESULTS: In cross-sectional analyses, mean total testosterone levels were 413.9 ± 180.0, with considerable variation among participants. In 21.4%, total testosterone levels were <275 ng/dL. Similarly, directly measured free testosterone levels were low (<6.6 ng/dL) in 37.6%. Total testosterone levels were modestly correlated with directly measured free testosterone, estradiol, estrone, DHT, and SHBG, and weakly negatively associated with body mass index and smoking. In longitudinal analyses (n = 215), average total testosterone, estradiol, and estrone levels decreased, whereas SHBG increased, but changes were highly variable. Among those with total testosterone > 275 ng/dL at baseline, testosterone levels decreased to <275 ng/dL in 20.5%. CONCLUSION: In old men, there was a broad range of total testosterone levels, and a significant fraction were in a range considered hypogonadal. In longitudinal analyses, although there was considerable interindividual variation, gradual declines in mean total testosterone continued in the 8th through 10th decades of life.

Association of testosterone-induced increase in neutrophil and monocyte counts with thromboembolic events: The TRAVERSE trial

American Heart Journal · 2025-04-15 · 6 citations

SAT-156 Associations of Testosterone, Dihydrotestosterone and Sex Hormone-binding Globulin with Risks of Cancer Death, Incident Cancer, and Incident Prostate Cancer in Men. Individual Participant Data Meta-analyses

Journal of the Endocrine Society · 2025-10-01

Abstract Disclosure: R.J. Marriott: None. K. Murray: None. L. Antonio: None. S. Bhasin: None. A.S. Dobs: None. L. Flicker: None. D.J. Handelsman: None. G.J. Hankey: None. R. Wilkening: None. A.M. Matsumoto: None. C. Ohlsson: None. E.S. Orwoll: None. D.M. Vanderschueren: None. H.W. Vesper: None. G.A. Wittert: None. F.C. Wu: None. B.B. Yeap: None. Aims: Whether differences in sex hormones relate to cancer, particularly prostate cancer, risk in men remains uncertain. We sought to clarify associations of testosterone, dihydrotestosterone and sex hormone-binding globulin (SHBG) with cancer risk via individual participant data (IPD) meta-analyses of major prospective cohort studies of community-dwelling men with testosterone measured using mass spectrometry. Methods: Eligible studies were identified via systematic literature review to July 2019, with bridge searches to March 2024. Ten studies provided IPD (24,510 men; 276,931 participant-years; 2847 cancer deaths), one provided aggregate data (1535 men; 184 cancer deaths). Five studies provided IPD for incident prostate cancer (12,280 men; 151,373 participant-years; 918 events). Two-stage random effects meta-analyses controlled for age, prior cancer, BMI, marital status, alcohol, smoking, physical activity, hypertension and diabetes. Results: Men with baseline testosterone at or below the lowest quintile median (Q1; 8.2 nmol/L), had higher risk of cancer death relative to Q5 (Q1:Q5 hazard ratio [HR]=1.15, 95% confidence interval [CI]=1.01-1.31). Baseline testosterone was not associated with risk of incident non-fatal and fatal cancer, nor incident prostate cancer. Men with lower baseline dihydrotestosterone had a higher risk of cancer death (Q1:Q5 HR=1.21, 95%CI=1.04-1.41), but not incident fatal and non-fatal cancer. SHBG was non-linearly associated with risk of cancer death (Q3:Q5 HR=0.79, 95%CI=0.66-0.95; Q4:Q5 HR=0.85, 95%CI=0.76-0.96). SHBG was not associated with incident non-fatal and fatal cancer. Men with lower baseline SHBG had higher risk of incident prostate cancer (Q1:Q5, HR=1.31, 95%CI=1.08-1.60; Q2:Q5 HR=1.26, 95%CI=1.04-1.52). Relative heterogeneity was negligible to moderate (estimates of I2 had 95%CI from 0.0-65.4%). Summary estimates from IPD were robust to the inclusion of aggregate data. Conclusions: Men with lower testosterone or dihydrotestosterone concentrations had higher risk, and men with mid-range SHBG lower risk, of cancer death. Testosterone was not associated with prostate cancer risk, while men with lower SHBG had a higher risk of incident prostate cancer. Testosterone, dihydrotestosterone and SHBG are biomarkers for cancer risk. The association between SHBG and prostate cancer risk merits further evaluation. Presentation: Saturday, July 12, 2025

The AFFIRM Framework for gender-affirming care: qualitative findings from the Transgender and Gender Diverse Health Equity Study

BMC Public Health · 2025-02-06 · 12 citations

BACKGROUND: Transgender, nonbinary, and gender diverse (TGD) people experience stigma in healthcare settings impacting healthcare utilization, including avoidance of care due to anticipated discrimination. Gender-affirming care refers to care for medical gender affirmation, such as gender-affirming hormones and surgery, as well as general care that affirms and respects TGD patients. This study sought to explore the experiences of TGD adults to inform gender-affirming care delivery and develop an actionable framework for practice. METHODS: Between May-October 2021, one-time individual in-depth interviews were conducted with 27 TGD adults receiving any healthcare in the greater Boston Massachusetts area to gather data about gender-affirming care. Interviews were semi-structured, explored prior and current experiences in healthcare and ideal gender-affirming care models, and conducted virtually via a secure Zoom platform. Analyses were conducted using immersion crystallization and reflexive thematic analysis; interview transcripts were double coded by two coders. RESULTS: Participants had a mean age of 28.5, ranging 18-45 years, and were: 7 transgender men, 6 transgender women, 8 nonbinary, 3 genderqueer, 1 agender, and 2 gender not specified. Themes about gender-affirming care coalesced into the acronym AFFIRM: (1) Affirms in individual interactions: Participants called for affirmation of TGD identity, lived expertise, and competent TGD providers and staff. (2) Flexible and accessible: Participants expressed the need for gender-affirming care to be available beyond urban population-specific clinics, in a timely fashion without long wait lists, and in a community-centered manner such as offering non-traditional times and settings. (3) Fights systemic oppression: Participants emphasized the need for providers and health systems to eliminate gatekeeping practices for gender-affirming care and create care models that resist intersecting oppressive systems such as racism and cisgenderism. (4) Interacts with community: Patients desired intentional interaction with TGD community to holistically address health and unmet gender affirmation needs. (5) Retains patients in care: Patients shared the need to collaboratively identify and problem-solve obstacles to gender-affirming care with providers and healthcare systems to optimize TGD-specific retention strategies. (6) Multidisciplinary: Patients called for interdisciplinary teams with co-located services such as primary care and mental healthcare with letter-writing for surgical care, and incorporation of peer navigators to meet the broader social, health, and well-being needs of TGD people. CONCLUSIONS: Findings from this study and the AFFIRM Framework which emerged from TGD patient narratives can be applied to improve current care and set benchmarks for high-quality gender-affirming care delivery and practice.