Impact of Testosterone Replacement Therapy on Immunological Functioning
The available evidence does not directly address the impact of testosterone replacement therapy on immunological functioning, as current guidelines and high-quality studies focus primarily on cardiovascular, sexual, prostate, and hematologic outcomes rather than immune system parameters.
Evidence Gap in Immunological Assessment
The major clinical guidelines and systematic reviews examining testosterone replacement therapy have not evaluated immunological functioning as a primary or secondary outcome:
- The 2018 AUA guideline on testosterone deficiency does not include immune function monitoring or assessment in its recommendations 1
- The 2020 American College of Physicians evidence report analyzed 38 randomized controlled trials but did not report on immunological outcomes, focusing instead on sexual function, quality of life, physical function, and cardiovascular safety 1
- The most recent 2024 systematic review with individual participant data meta-analysis (35 trials, 5601 participants) similarly did not assess immune parameters 2
What We Know About TRT's Systemic Effects
While immunological function is not directly studied, TRT produces several systemic changes that could theoretically affect immune function:
Hematologic Effects
- Erythrocytosis occurs in 3-18% of patients on transdermal formulations and up to 44% on injectable testosterone, which alters blood composition but has unknown effects on immune cell populations 3
- Hemoglobin and hematocrit levels consistently increase with TRT 2
Metabolic and Inflammatory Markers
- TRT shows no significant effect on C-reactive protein levels, a marker of systemic inflammation, even at supraphysiologic doses 1
- Lipid profiles remain largely neutral with physiologic testosterone replacement 1
Cardiovascular and Thrombotic Considerations
- Studies examining prothrombotic factors, prothrombinase activity, and proteins C and S showed that decreases appeared counterbalanced by increases in antithrombin III activity and fibrinolytic activity, with no effect on platelet activity 1
- These coagulation changes suggest some impact on blood-based immune and inflammatory pathways, though clinical significance for immune function remains undefined 1
Clinical Monitoring Does Not Include Immune Parameters
Current evidence-based monitoring recommendations focus on:
- Hematocrit/hemoglobin at baseline and follow-up 3
- PSA levels and prostate assessment 1, 3
- Cardiovascular risk factors 3
- Sleep apnea screening 3
No guideline recommends monitoring immune function markers such as lymphocyte counts, immunoglobulin levels, or inflammatory cytokines during TRT 1, 3.
What This Means for Clinical Practice
Given the absence of evidence on immunological functioning:
- Do not assume TRT has clinically significant effects on immune function based on current evidence 1, 2
- Standard monitoring protocols do not require immune function testing unless clinically indicated for other reasons 1, 3
- If immune function assessment is needed for a specific clinical scenario (e.g., recurrent infections, autoimmune disease), this should be evaluated independently of TRT status using standard immunological workup
- The 2024 TestES evidence synthesis specifically noted that rigorous long-term evidence is needed to assess multiple aspects of TRT safety, which would include immune function if it becomes a concern 2
Critical Caveat
The lack of evidence does not prove TRT has no effect on immune function—it simply means this outcome has not been systematically studied in the clinical trials that form the basis of current guidelines 1, 2. Any clinical decisions regarding TRT in immunocompromised patients or those with immune-mediated conditions must be made based on individual risk-benefit assessment rather than evidence-based recommendations, as this specific population and outcome combination has not been adequately researched 1.