Testosterone replacement therapy in blood donors modulates erythrocyte metabolism and susceptibility to hemolysis in cold storage

Abstract

Background: Red blood cells (RBCs) derived from patients who receive testosterone replacement therapy (TRT) may be considered eligible for component production and transfusion. The aim of this study was to identify testosteronedependent changes in RBC metabolism and to evaluate its impact on susceptibility to hemolysis during cold storage. Study Design and Methods: We characterized stored RBCs from two cohorts of TRT patients who were matched with control donors (no TRT) based upon sex, age, and ethnicity. We further evaluated the impact of testosterone deficiency (orchiectomy) on RBC metabolism in FVB/NJ mice. RBC metabolites were quantified by ultra-high-pressure liquid chromatography-mass spectrometry. RBC storage stability was determined in RBC units from TRT and controls by quantifying storage, osmotic, and oxidative hemolysis. Results: Orchiectomy in mice was associated with significant (P < 0.05) changes in RBC metabolism as compared with intact males including increased levels of acyl-carnitines, long-chain fatty acids (eg, docosapentaenoic acids), arginine, and dopamine. Stored RBCs from TRT patients exhibited higher levels of pentose phosphate pathway metabolites, glutathione, and oxidized purines (eg, hypoxanthine), suggestive of increased activation of antioxidant pathways in this group. Further analyses indicated significant changes in free fatty acids and acyl-carnitines in response to testosterone therapies. With regard to hemolysis, TRT was associated with enhanced susceptibility to osmotic hemolysis. Correlation analyses identified acyl-carnitines as significant modifiers of RBC predisposition to osmotic and oxidative hemolysis. Conclusions: These observations provide new insights into testosteronemediated changes in RBC metabolome and biology that may impact the storage capacity and posttransfusion efficacy of RBCs from TRT donors.

Acute Cycling Exercise Induces Changes in Red Blood Cell Deformability and Membrane Lipid Remodeling

“…As such, these results support a model of accelerated RBC aging in vivo caused by persistent exercise, which would result in accelerated removal from circulation of RBCs with limited functional capability. The resultant shorter RBC circulatory lifespans would require enhanced erythropoiesis to generate a population of younger cells that are better equipped to face oxidant challenges, at least in the case of aging in vivo [ 77 , 78 ] and in vitro [ 79 ] in a subject age- and gender-dependent fashion [ 80 , 81 ]. Future studies should focus on understanding whether exercise training itself can also generate more robust RBCs that are able to cope with a “harsher” environment.…”

Proteinuric chronic kidney disease is associated with altered red blood cell lifespan, deformability and metabolism

“…While those results were generated ex vivo, we report here similar responses in vivo. Furthermore, acylcarnitines are capable of directly modulating membrane properties 45 and correlate with RBC deformability 46 , as well as osmotic and oxidative hemolysis 47 . Unconjugated free carnitine promotes membrane deformability through the mediation of interactions between membrane proteins 48 .…”

Unique plasma metabolite signature for adolescents with Klinefelter syndrome reveals altered fatty acid metabolism

“…In direct comparison, red blood cell metabolites from blood donors on testosterone replacement therapy analyzed in the same laboratory used in this study revealed significant differences compared to blood from male donors not on testosterone, suggesting increased activation of antioxidant pathways and higher acylcarnitines. 28 Our results may underestimate the impact of testosterone treatment on the metabolome due to our small sample size, significant heterogeneity in the testosterone-treated group due to diverse clinical management, and no differences in serum testosterone concentrations between treated and untreated groups (suggesting all were eugonadal either endogenously or with treatment). Nonetheless, exogenous testosterone in adolescent males with KS seems to have a minimal influence on the plasma metabolome and does not normalize the striking metabolic disparities observed between KS and controls.…”

“…6 Of particular relevance to KS, metabolomics has been extensively used in characterizing cardiometabolic-related disease states, including metabolic syndrome and type 2 diabetes, 7 as well as in the setting of male hypogonadism with testosterone-replacement therapy. 8 Analysis of circulating levels of substrates and intermediate metabolites from intra-mitochondrial pathways, particularly ß- oxidation of fatty acids, offers a non-invasive assessment of mitochondrial metabolism – a viable strategy to predict intracellular metabolic states from extracellular metabolomics data. 9 When fatty acid oxidation is impaired, as in the case with multiple cardiometabolic disorders, the reliance on protein catabolism to provide tricarboxcylic acid (TCA) cycle intermediates increases.…”