Abstract A080: Male-biased metabolic and structural muscular changes driven by testosterone flare-like conditions

Abstract Background: During the first 1 to 3 weeks of LHRH-agonist therapy for recurrent or metastatic prostate cancer, an initial increase in testosterone is associated with a condition known as "flare." Flare often is accompanied by fatigue, increases in immune infiltrate in prostate cancer and cardiovascular distress. Cardiovascular myopathies and fatigue have been associated with chronic inflammatory responses and activated cell-mediated immunity. Methods and Results: Using a model of autoimmune mice with persistent low-level expression of proinflammatory interferon gamma (IFN-g), we found fatigue and aberrant cardiovascular activity in the form of reduced ejection fraction responding to exercise in male but not female mice. This finding suggests that male hormone has a potential role for impacting cardiovascular fatigue with a more activated immune environment. Furthermore, analysis of cardiovascular tissues revealed an increase in factors associated with fatigue, such as lactic acid production and changes in expression of genes associated with an increase in anaerobic respiration and poor mitochondrial performance in cardiac musculature. Conclusion: These results indicate that the chronic expression of IFN-g may be synergetic with androgen to produce a male-biased fatigue and muscle dysfunction. Considering that the most frequent side effects to activated immune therapies to cancer in males undergoing CAR-T therapies are fatigue and cardiomyopathies we believe this insight may be beneficial to patients of other therapies as well. Understanding the biological effects of therapy driven flare may offer opportunities for physiological interventions in patients undergoing persistent or intermittent LHRHa therapy. Citation Format: John M. Fenimore, Danielle Springer, Elijah Edmonston, Kunio Nagashima, Adam Sowalsky, Howard Young. Male-biased metabolic and structural muscular changes driven by testosterone flare-like conditions [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A080.