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Testosterone and androgen receptor pathway modulation in sepsis: immunometabolic mechanisms and therapeutic
Mateusz Szczupak1, Jacek Kobak2,3, Mateusz Kreczko4,5
1Department of Anesthesiology and Intensive Therapy, Copernicus Hospital in Gdańsk, Gdańsk, Poland.
Introduction:
Sepsis remains a major challenge in intensive care medicine, characterized by a dysregulated host response to infection and high mortality. Increasing evidence highlights complex interactions among the endocrine, immune, and metabolic systems, including a potential role of testosterone in modulating the immunometabolic response.
Aim:
To systematically map and synthesize current evidence on the role of testosterone as a potential modulator of the immunometabolic response in sepsis.
Materials And Methods:
A scoping review was conducted in accordance with the Joanna Briggs Institute methodology and PRISMA-ScR guidelines. PubMed, Scopus, Web of Science, Cochrane Library, and EBSCO were searched for studies published between 2015 and 2025. Eligible studies included adult patients with sepsis or septic shock and investigated testosterone levels, androgen receptor activity, or androgen-based interventions. All study designs, including case reports, were considered.
Results:
Thirteen studies met the inclusion criteria. The majority of studies reported lower testosterone levels in patients with higher disease severity, reflected by higher SOFA and APACHE II scores, and in non-survivors compared with survivors. Experimental and translational studies have demonstrated that the androgen receptor (AR) pathway regulates cytokine production and immune cell metabolism. Clinical studies evaluating testosterone supplementation reported changes in selected metabolic and clinical parameters; however, no statistically significant improvement in survival was observed.
Conclusion:
Testosterone and the androgen receptor pathway may contribute to immunometabolic dysregulation in sepsis. Testosterone deficiency is associated with greater disease severity and increased mortality; however, current evidence does not support the routine use of androgen therapy. Further well-designed translational and clinical studies, incorporating sex-specific analyses, baseline hormonal status, and multi-omics approaches, are required to enable personalized hormonal interventions in sepsis.
