Background:
Please read this previous article:
New Data: https://www.sciencedirect.com/science/article/abs/pii/S0002870325001206
The associations between TRT-induced increases in neutrophils and monocytes and higher risk of venous thromboembolism and cardiac events suggest that monitoring these parameters may improve risk stratification. Similarly, the increased incidence of cardiac arrhythmias underscores the importance of cardiac monitoring in TRT patients.
Clinicians should incorporate these findings into their risk assessment and patient counseling when considering testosterone therapy, particularly in men with pre-existing cardiovascular risk factors. Monitoring of complete blood counts, with special attention to neutrophil and monocyte levels, may become an increasingly important component of care for men receiving testosterone replacement therapy.
Sources:
Association of Testosterone-Induced Increase in Neutrophil and Monocyte Counts with Thromboembolic Events: The TRAVERSE Trial: Testosterone-Induced Increase in Neutrophil and Monocyte Counts and VTE - PubMed
TRAVERSE Study Supports Cardiovascular Safety of Testosterone Therapy When Used as Indicated
TRAVERSE Trial: No Increased Cardiovascular Risk with Testosterone Replacement Therapy
Cardiovascular Safety of Testosterone-Replacement Therapy - American College of Cardiology
TRAVERSE Trial Insights: A Comprehensive Look at Testosterone Replacement Therapy and Cardiovascular Safety, Journal Club - Rashid Sayyid & Zachary Klaassen
Making Sense of the TRAVERSE Trials
Expansion of CD10neg neutrophils and CD14+HLA-DRneg/low monocytes driving proinflammatory responses in patients with acute myocardial infarction
https://ashpublications.org/thehema...tosterone-Therapy-in-Men-Doubles-the-Risk-for
FDA issues class-wide labeling changes for testosterone products
https://www.jacc.org/doi/10.1016/j.jacadv.2023.100742
https://www.ahajournals.org/doi/10.1161/ATVBAHA.123.316246
https://www.jacc.org/doi/10.1016/j.jacc.2016.12.022
Neutrophils as regulators of cardiovascular inflammation - Nature Reviews Cardiology
Frontiers | The roles of neutrophils in cardiovascular diseases
Role of Neutrophils in Cardiac Injury and Repair Following Myocardial Infarction - PMC
The neutrophil–lymphocyte ratio is associated with all-cause and cardiovascular mortality in cardiovascular patients - Scientific Reports
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.123.322757
Cardiovascular Safety of Testosterone-Replacement Therapy - American College of Cardiology
Testosterone therapy may be safe for men at risk for heart attack and stroke - Harvard Health
Research Finds Testosterone Therapy Safe for Heart Health | Cedars-Sinai
How Low Testosterone Affects the Heart
Testosterone and the Heart - PMC
TRAVERSE Study Supports Cardiovascular Safety of Testosterone Therapy When Used as Indicated
Cardiovascular Safety of Testosterone-Replacement Therapy - American College of Cardiology
Testosterone-replacement therapy does not increase cardiac events in men with hypogonadism - Nature Reviews Cardiology
Long Term Cardiovascular Safety of Testosterone Therapy: A Review of the TRAVERSE Study - PMC
Testosterone and Cardiovascular Risk: TRAVERSE Trial and New FDA Label Change
TRAVERSE Trial Insights: A Comprehensive Look at Testosterone Replacement Therapy and Cardiovascular Safety, Journal Club - Rashid Sayyid & Zachary Klaassen
https://wjmh.org/pdf/10.5534/wjmh.240081
TRAVERSE Study Supports Cardiovascular Safety of Testosterone Therapy When Used as Indicated
https://drmohitkhera.com/wp-content/uploads/2023/06/traverse-trial-methodology.pdf
Making Sense of the TRAVERSE Trials
Long Term Cardiovascular Safety of Testosterone Therapy: A Review of the TRAVERSE Study - PMC
TRAVERSE Trial: Urology Research with Dr. Mohit Khera
Efficacy of Testosterone Replacement Therapy in Correcting Anemia in Men With Hypogonadism: A Randomized Clinical Trial - PMC
Cardiovascular Safety of Testosterone-Replacement Therapy - American College of Cardiology
https://www.jacc.org/doi/10.1016/j.jacc.2021.06.022
TRAVERSE Study Supports Cardiovascular Safety of Testosterone Therapy When Used as Indicated
TRAVERSE Trial Insights: A Comprehensive Look at Testosterone Replacement Therapy and Cardiovascular Safety, Journal Club - Rashid Sayyid & Zachary Klaassen
FDA Issues New Labeling Changes Clarifying Safety of Testosterone Products Following Clinical Trials
Testosterone and Cardiovascular Risk: TRAVERSE Trial and New FDA Label Change
New Changes in Testosterone Product Labeling
FDA Drops Testosterone's Boxed Warning on Heart Attack, Stroke Risk
FDA Removes Black Box Warning on TRT: What You Need to Know
FDA issues class-wide labeling changes for testosterone products
FDA issues labeling changes for testosterone products following TRAVERSE, postmarket studies
FDA recommends removing black box warning for CV risk from all testosterone product labels
Please read this previous article:
Heart palpitations and AFIB (Atrial Fibrillation) risk in older men using testosterone is examined in the video below.
Highlights
[
] Testosterone use in older men and its link to heart palpitations and AFIB.
[] Research findings suggest a potential association between testosterone therapy and heart rhythm disturbances.
[] Discussion about the need for cautious testosterone administration in older male patients.
[
] Insights into the mechanisms through which testosterone might impact heart health.
[] Examination of existing studies to assess the credibility of the...
Highlights
[
] Testosterone use in older men and its link to heart palpitations and AFIB.[] Research findings suggest a potential association between testosterone therapy and heart rhythm disturbances.
[] Discussion about the need for cautious testosterone administration in older male patients.
[
] Insights into the mechanisms through which testosterone might impact heart health.[] Examination of existing studies to assess the credibility of the...
New Data: https://www.sciencedirect.com/science/article/abs/pii/S0002870325001206
Neutrophil and Monocyte Changes in Testosterone Therapy: New TRAVERSE Trial Findings on Cardiovascular Risk
The TRAVERSE (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men) trial has provided significant new insights into testosterone replacement therapy (TRT) safety, particularly regarding its hematological effects and associated cardiovascular risks. Recent analyses exploring the relationship between TRT-induced blood cell changes and adverse cardiovascular outcomes offer important considerations for clinical practice. This report examines these findings and their implications for risk assessment in testosterone therapy.Hematological Effects of Testosterone Therapy
The TRAVERSE trial enrolled 5,204 men aged 45-80 years with hypogonadism and preexisting or increased risk of cardiovascular disease (CVD), randomizing them to receive either transdermal testosterone or placebo gel daily for up to 5 years2. While previous analyses showed TRT was noninferior to placebo regarding major adverse cardiovascular events (MACE) 167, recent findings reveal significant effects on blood cell populations.Specific Cell Population Changes
TRT was associated with distinct shifts in blood cell populations compared to placebo:- Significant increases in neutrophil counts
- Significant increases in monocyte counts
- Decreases in lymphocyte counts
- Decreases in platelet counts2
Association Between Cell Count Changes and Venous Thromboembolism
One of the most clinically significant discoveries from this analysis was the relationship between specific cell count changes and venous thromboembolism (VTE) risk.Neutrophil and Monocyte Increases Linked to VTE
The data showed statistically significant associations between cell count changes and VTE risk:- For each standard deviation increase in neutrophil count, the odds of VTE increased by 32% (OR 1.32 [1.01, 1.73])2
- For each standard deviation increase in monocyte count, the odds of VTE increased by 39% (OR 1.39 [1.08, 1.79])2
Cell Counts and Major Adverse Cardiovascular Events
Beyond VTE risk, the analysis also revealed associations between neutrophil and monocyte counts and the risk of major adverse cardiovascular events.Baseline and Treatment-Period Cell Counts
Both baseline cell counts and on-treatment cell counts showed significant relationships with MACE risk:- Baseline neutrophil counts: OR 1.18 [1.06, 1.31] per standard deviation increase2
- Baseline monocyte counts: OR 1.16 [1.05, 1.29] per standard deviation increase2
- On-treatment neutrophil counts: OR 1.25 [1.12, 1.40] per standard deviation increase2
- On-treatment monocyte counts: OR 1.18 [1.06, 1.31] per standard deviation increase2
Arrhythmias and Other Cardiac Effects
While the neutrophil and monocyte findings have garnered attention, the TRAVERSE trial also documented increased rates of cardiac rhythm disturbances in testosterone-treated patients.Increased Arrhythmia Risk
Several specific cardiac rhythm abnormalities were more common in the testosterone group:- Nonfatal arrhythmias warranting intervention: 5.2% in the testosterone group vs. 3.3% in the placebo group11
- Atrial fibrillation: 3.5% in the testosterone group vs. 2.4% in the placebo group615
Biological Mechanisms and Pathophysiology
The observed associations between neutrophil/monocyte changes and cardiovascular events warrant consideration of potential biological mechanisms. While the TRAVERSE trial wasn't designed to elucidate specific pathways, other research provides relevant context.Neutrophils in Cardiovascular Disease
Research has shown that neutrophils can be recruited to sites of cardiac injury, with immature neutrophils potentially playing a role in inflammatory responses in cardiovascular tissue4. Neutrophils with higher expression of matrix-degrading proteases like MMP-9 may contribute to tissue remodeling and potentially to thrombus formation4.Implications for Inflammatory Processes
The shift toward increased neutrophils and monocytes with decreased lymphocytes suggests TRT may induce a pro-inflammatory state that could contribute to both atherosclerotic progression and thrombotic events. This aligns with observations that inflammatory markers are often elevated in patients with cardiovascular disease.Clinical Implications for TRT Risk Assessment
These new findings have important implications for clinical practice and risk stratification in patients considering TRT.Risk Stratification Before Initiating Therapy
Before initiating TRT, clinicians should consider:- Baseline neutrophil and monocyte counts as potential risk markers
- Pre-existing cardiovascular risk factors
- History of thromboembolic events, particularly in light of findings that TRT potentially doubles VTE risk5
Monitoring During Therapy
During TRT, monitoring should include:- Regular assessment of complete blood counts with differential
- Vigilance for symptoms of VTE or cardiac arrhythmias
- Consideration of dose adjustments or discontinuation if significant increases in neutrophil or monocyte counts occur
Regulatory Response and Practice Changes
The TRAVERSE trial has already influenced regulatory guidance on testosterone therapy. In February 2025, the FDA updated labeling for testosterone products, removing language from the Boxed Warning related to increased risk of adverse cardiovascular outcomes, while maintaining warnings about blood pressure increases1214.Current FDA Position
The FDA now requires:- Addition of TRAVERSE trial results to all testosterone product labeling
- Retaining "Limitation of Use" language for age-related hypogonadism
- Removal of language about increased cardiovascular risk from the Boxed Warning
- Addition of product-specific information on increased blood pressure12
Study Limitations and Controversies
Despite its size and rigorous design, the TRAVERSE trial has limitations that warrant consideration when interpreting these findings.Implementation Challenges
Some critics have noted significant limitations:- High discontinuation rates (>60% in both the testosterone and placebo groups)
- Shorter than planned treatment duration (mean of 22 months versus planned 5 years)
- Barely achieved target testosterone levels in many participants10
Biological Variability
The relationship between neutrophil/monocyte counts and cardiovascular events may be complex and influenced by many factors beyond TRT, including:- Underlying inflammatory conditions
- Concurrent medications
- Genetic factors affecting hematopoiesis
Conclusion
The latest findings from the TRAVERSE trial provide important new insights into how testosterone replacement therapy affects hematological parameters and how these changes relate to cardiovascular risk. While the overall noninferiority of TRT for major adverse cardiovascular events has been established, these new data highlight specific mechanisms and risk factors that require clinical attention.The associations between TRT-induced increases in neutrophils and monocytes and higher risk of venous thromboembolism and cardiac events suggest that monitoring these parameters may improve risk stratification. Similarly, the increased incidence of cardiac arrhythmias underscores the importance of cardiac monitoring in TRT patients.
Clinicians should incorporate these findings into their risk assessment and patient counseling when considering testosterone therapy, particularly in men with pre-existing cardiovascular risk factors. Monitoring of complete blood counts, with special attention to neutrophil and monocyte levels, may become an increasingly important component of care for men receiving testosterone replacement therapy.
Sources:
Association of Testosterone-Induced Increase in Neutrophil and Monocyte Counts with Thromboembolic Events: The TRAVERSE Trial: Testosterone-Induced Increase in Neutrophil and Monocyte Counts and VTE - PubMed
TRAVERSE Study Supports Cardiovascular Safety of Testosterone Therapy When Used as Indicated
TRAVERSE Trial: No Increased Cardiovascular Risk with Testosterone Replacement Therapy
Cardiovascular Safety of Testosterone-Replacement Therapy - American College of Cardiology
TRAVERSE Trial Insights: A Comprehensive Look at Testosterone Replacement Therapy and Cardiovascular Safety, Journal Club - Rashid Sayyid & Zachary Klaassen
Making Sense of the TRAVERSE Trials
Expansion of CD10neg neutrophils and CD14+HLA-DRneg/low monocytes driving proinflammatory responses in patients with acute myocardial infarction
https://ashpublications.org/thehema...tosterone-Therapy-in-Men-Doubles-the-Risk-for
FDA issues class-wide labeling changes for testosterone products
https://www.jacc.org/doi/10.1016/j.jacadv.2023.100742
https://www.ahajournals.org/doi/10.1161/ATVBAHA.123.316246
https://www.jacc.org/doi/10.1016/j.jacc.2016.12.022
Neutrophils as regulators of cardiovascular inflammation - Nature Reviews Cardiology
Frontiers | The roles of neutrophils in cardiovascular diseases
Role of Neutrophils in Cardiac Injury and Repair Following Myocardial Infarction - PMC
The neutrophil–lymphocyte ratio is associated with all-cause and cardiovascular mortality in cardiovascular patients - Scientific Reports
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.123.322757
Cardiovascular Safety of Testosterone-Replacement Therapy - American College of Cardiology
Testosterone therapy may be safe for men at risk for heart attack and stroke - Harvard Health
Research Finds Testosterone Therapy Safe for Heart Health | Cedars-Sinai
How Low Testosterone Affects the Heart
Testosterone and the Heart - PMC
TRAVERSE Study Supports Cardiovascular Safety of Testosterone Therapy When Used as Indicated
Cardiovascular Safety of Testosterone-Replacement Therapy - American College of Cardiology
Testosterone-replacement therapy does not increase cardiac events in men with hypogonadism - Nature Reviews Cardiology
Long Term Cardiovascular Safety of Testosterone Therapy: A Review of the TRAVERSE Study - PMC
Testosterone and Cardiovascular Risk: TRAVERSE Trial and New FDA Label Change
TRAVERSE Trial Insights: A Comprehensive Look at Testosterone Replacement Therapy and Cardiovascular Safety, Journal Club - Rashid Sayyid & Zachary Klaassen
https://wjmh.org/pdf/10.5534/wjmh.240081
TRAVERSE Study Supports Cardiovascular Safety of Testosterone Therapy When Used as Indicated
https://drmohitkhera.com/wp-content/uploads/2023/06/traverse-trial-methodology.pdf
Making Sense of the TRAVERSE Trials
Long Term Cardiovascular Safety of Testosterone Therapy: A Review of the TRAVERSE Study - PMC
TRAVERSE Trial: Urology Research with Dr. Mohit Khera
Efficacy of Testosterone Replacement Therapy in Correcting Anemia in Men With Hypogonadism: A Randomized Clinical Trial - PMC
Cardiovascular Safety of Testosterone-Replacement Therapy - American College of Cardiology
https://www.jacc.org/doi/10.1016/j.jacc.2021.06.022
TRAVERSE Study Supports Cardiovascular Safety of Testosterone Therapy When Used as Indicated
TRAVERSE Trial Insights: A Comprehensive Look at Testosterone Replacement Therapy and Cardiovascular Safety, Journal Club - Rashid Sayyid & Zachary Klaassen
FDA Issues New Labeling Changes Clarifying Safety of Testosterone Products Following Clinical Trials
Testosterone and Cardiovascular Risk: TRAVERSE Trial and New FDA Label Change
New Changes in Testosterone Product Labeling
FDA Drops Testosterone's Boxed Warning on Heart Attack, Stroke Risk
FDA Removes Black Box Warning on TRT: What You Need to Know
FDA issues class-wide labeling changes for testosterone products
FDA issues labeling changes for testosterone products following TRAVERSE, postmarket studies
FDA recommends removing black box warning for CV risk from all testosterone product labels
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