title: Testosterone-dependent sex differences in red blood cell hemolysis in storage, stress, and disease.
abstract: BACKGROUND
  Red blood cell (RBC) hemolysis represents an intrinsic mechanism for human vascular disease. Intravascular hemolysis releases hemoglobin and other metabolites that inhibit nitric oxide signaling and drive oxidative and inflammatory stress. Although these pathways are important in disease pathogenesis, genetic and population modifiers of hemolysis, including sex, have not been established.
  
  
  METHODS
  We studied sex differences in storage or stress-induced hemolysis in RBC units from the United States and Canada in 22 inbred mouse strains and in patients with sickle cell disease (SCD) using measures of hemolysis in 315 patients who had homozygous SS hemoglobin from the Walk-PHASST cohort. A mouse model also was used to evaluate posttransfusion recovery of stored RBCs, and gonadectomy was used to determine the mechanisms related to sex hormones.
  
  
  RESULTS
  An analysis of predisposition to hemolysis based on sex revealed that male RBCs consistently exhibit increased susceptibility to hemolysis compared with females in response to routine cold storage, under osmotic or oxidative stress, after transfusion in mice, and in patients with SCD. The sex difference is intrinsic to the RBC and is not mediated by plasmatic factors or female sex hormones. Importantly, orchiectomy in mice improves RBC storage stability and posttransfusion recovery, whereas testosterone repletion therapy exacerbates hemolytic response to osmotic or oxidative stress.
  
  
  CONCLUSIONS
  Our findings suggest that testosterone increases susceptibility to hemolysis across human diseases, suggesting that male sex may modulate clinical outcomes in blood storage and SCD and establishing a role for donor genetic variables in the viability of stored RBCs and in human hemolytic diseases.
authors: Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania. tak77@pitt.edu.|Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. tak77@pitt.edu.
authors: Tamir
authors: T
authors: Kanias
authors: Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Derek
authors: D
authors: Sinchar
authors: Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: David
authors: D
authors: Osei-Hwedieh
authors: Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Jeffrey J
authors: JJ
authors: Baust
authors: Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.|Canadian Blood Services, Centre for Innovation, Edmonton, Alberta, Canada.
authors: Andrew
authors: A
authors: Jordan
authors: Bloodworks NW Research Institute, University of Washington School of Medicine, Seattle, Washington.|Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington.|Department of Medicine, Division of Hematology, University of Washington School of Medicine, Seattle, Washington.
authors: James C
authors: JC
authors: Zimring
authors: Bloodworks NW Research Institute, University of Washington School of Medicine, Seattle, Washington.
authors: Hayley R
authors: HR
authors: Waterman
authors: Bloodworks NW Research Institute, University of Washington School of Medicine, Seattle, Washington.
authors: Karen S
authors: KS
authors: de Wolski
authors: Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.|Canadian Blood Services, Centre for Innovation, Edmonton, Alberta, Canada.
authors: Jason P
authors: JP
authors: Acker
authors: Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.|Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Mark T
authors: MT
authors: Gladwin
mesh_terms: D000328:Adult; D000367:Age Factors; D000818:Animals; D001793:Blood Preservation; D002170:Canada; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006461:Hemolysis; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D009997:Osmotic Pressure; D018384:Oxidative Stress; D012737:Sex Factors; D013739:Testosterone / Q000494:pharmacology*; D014481:United States
chemical_list: D013739:Testosterone