The influence of sex steroid hormones on the response to trauma and burn injury

K Al-Tarrah, N Moiemen, J M Lord, K Al-Tarrah, N Moiemen, J M Lord

Abstract

Trauma and related sequelae result in disturbance of homeostatic mechanisms frequently leading to cellular dysfunction and ultimately organ and system failure. Regardless of the type and severity of injury, gender dimorphism in outcomes following trauma have been reported, with females having lower mortality than males, suggesting that sex steroid hormones (SSH) play an important role in the response of body systems to trauma. In addition, several clinical and experimental studies have demonstrated the effects of SSH on the clinical course and outcomes following injury. Animal studies have reported the ability of SSH to modulate immune, inflammatory, metabolic and organ responses following traumatic injury. This indicates that homeostatic mechanisms, via direct and indirect pathways, can be maintained by SSH at local and systemic levels and hence result in more favourable prognosis. Here, we discuss the role and mechanisms by which SSH modulates the response of the body to injury by maintaining various processes and organ functions. Such properties of sex hormones represent potential novel therapeutic strategies and further our understanding of current therapies used following injury such as oxandrolone in burn-injured patients.

Keywords: Burn; Estradiol; Oestrogen; Sex hormones; Sex steroid hormones; Testosterone; Trauma.

Conflict of interest statement

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Competing interests

The authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
The influence of SSH on the human body response following injury

References

    1. Haider AH, Crompton JG, Oyetunji T, Stevens KA, Efron DT, Kieninger AN, et al. Females have fewer complications and lower mortality following trauma than similarly injured males: a risk adjusted analysis of adults in the National Trauma Data Bank. Surgery. 2009;146(2):308–315. doi: 10.1016/j.surg.2009.05.006.
    1. Moore EC, Pilcher D, Bailey M, Cleland H. Women are more than twice as likely to die from burns as men in Australia and New Zealand: an unexpected finding of the Burns Evaluation And Mortality (BEAM) Study. J Crit Care. 2014;29(4):594–598. doi: 10.1016/j.jcrc.2014.03.021.
    1. McGowan JE, Jr, Barnes MW, Finland M. Bacteremia at Boston City Hospital: Occurrence and mortality during 12 selected years (1935-1972), with special reference to hospital-acquired cases. J Infect Dis. 1975;132(3):316–335. doi: 10.1093/infdis/132.3.316.
    1. Wearn C, Hardwicke J, Kitsios A, Siddons V, Nightingale P, Moiemen N. Outcomes of burns in the elderly: revised estimates from the Birmingham Burn Centre. Burns. 2015;41(6):1161–1168. doi: 10.1016/j.burns.2015.04.008.
    1. Lord JM, Midwinter MJ, Chen YF, Belli A, Brohi K, Kovacs EJ, et al. The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet. 2014;384(9952):1455–1465. doi: 10.1016/S0140-6736(14)60687-5.
    1. Sobrino J, Shafi S. Timing and causes of death after injuries. Proc (Baylor Univ Med Cent) 2013;26(2):120–123.
    1. Liu T, Xie J, Yang F, Chen JJ, Li ZF, Yi CL, et al. The influence of sex on outcomes in trauma patients: a meta-analysis. Am J Surg. 2015;210(5):911–921. doi: 10.1016/j.amjsurg.2015.03.021.
    1. Gannon CJ, Pasquale M, Tracy JK, McCarter RJ, Napolitano LM. Male gender is associated with increased risk for postinjury pneumonia. Shock. 2004;21(5):410–414. doi: 10.1097/00024382-200405000-00003.
    1. George RL, McGwin G, Jr, Windham ST, Melton SM, Metzger J, Chaudry IH, et al. Age-related gender differential in outcome after blunt or penetrating trauma. Shock. 2003;19(1):28–32. doi: 10.1097/00024382-200301000-00006.
    1. Offner PJ, Moore EE, Biffl WL. Male gender is a risk factor for major infections after surgery. Arch Surg. 1999;134(9):935–938. doi: 10.1001/archsurg.134.9.935.
    1. Schroder J, Kahlke V, Staubach KH, Zabel P, Stuber F. Gender differences in human sepsis. Arch Surg. 1998;133(11):1200–1205. doi: 10.1001/archsurg.133.11.1200.
    1. Haider AH, Crompton JG, Chang DC, Efron DT, Haut ER, Handly N, et al. Evidence of hormonal basis for improved survival among females with trauma-associated shock: an analysis of the National Trauma Data Bank. J Trauma. 2010;69(3):537–540. doi: 10.1097/TA.0b013e3181efc67b.
    1. Trentzsch H, Lefering R, Nienaber U, Kraft R, Faist E, Piltz S. The role of biological sex in severely traumatized patients on outcomes: a matched-pair analysis. Ann Surg. 2015;261(4):774–780. doi: 10.1097/SLA.0000000000000789.
    1. McKinley BA, Kozar RA, Cocanour CS, Valdivia A, Sailors RM, Ware DN, et al. Standardized trauma resuscitation: female hearts respond better. Arch Surg. 2002;137(5):578–583. doi: 10.1001/archsurg.137.5.578.
    1. Deitch EA, Livingston DH, Lavery RF, Monaghan SF, Bongu A, Machiedo GW. Hormonally active women tolerate shock-trauma better than do men: a prospective study of over 4000 trauma patients. Ann Surg. 2007;246(3):447–453. doi: 10.1097/SLA.0b013e318148566.
    1. Rappold JF, Coimbra R, Hoyt DB, Potenza BM, Fortlage D, Holbrook T, et al. Female gender does not protect blunt trauma patients from complications and mortality. J Trauma. 2002;53(3):436–441. doi: 10.1097/00005373-200209000-00007.
    1. Bowles BJ, Roth B, Demetriades D. Sexual dimorphism in trauma? A retrospective evaluation of outcome. Injury. 2003;34(1):27–31. doi: 10.1016/S0020-1383(02)00018-9.
    1. Coimbra R, Hoyt DB, Potenza BM, Fortlage D, Hollingsworth-Fridlund P. Does sexual dimorphism influence outcome of traumatic brain injury patients? The answer is no! J Trauma. 2003;54(4):689–700. doi: 10.1097/01.TA.0000058314.31655.5F.
    1. Gannon CJ, Napolitano LM, Pasquale M, Tracy JK, McCarter RJ. A statewide population-based study of gender differences in trauma: validation of a prior single-institution study. J Am Coll Surg. 2002;195(1):11–18. doi: 10.1016/S1072-7515(02)01187-0.
    1. Harbrecht BG, Peitzman AB, Rivera L, Heil B, Croce M, Morris JA, Jr, et al. Contribution of age and gender to outcome of blunt splenic injury in adults: multicenter study of the eastern association for the surgery of trauma. J Trauma. 2001;51(5):887–895. doi: 10.1097/00005373-200111000-00010.
    1. Holbrook TL, Hoyt DB, Anderson JP. The importance of gender on outcome after major trauma: functional and psychologic outcomes in women versus men. J Trauma. 2001;50(2):270–273. doi: 10.1097/00005373-200102000-00012.
    1. Napolitano LM, Greco ME, Rodriguez A, Kufera JA, West RS, Scalea TM. Gender differences in adverse outcomes after blunt trauma. J Trauma. 2001;50(2):274–280. doi: 10.1097/00005373-200102000-00013.
    1. Klein SL. Hormonal and immunological mechanisms mediating sex differences in parasite infection. Parasite Immunol. 2004;26(6-7):247–264. doi: 10.1111/j.0141-9838.2004.00710.x.
    1. Baue AE. MOF, MODS, and SIRS: what is in a name or an acronym? Shock. 2006;26(5):438–449. doi: 10.1097/01.shk.0000228172.32587.7a.
    1. Murphy TJ, Paterson HM, Kriynovich S, Zang Y, Kurt-Jones EA, Mannick JA, et al. Linking the "two-hit" response following injury to enhanced TLR4 reactivity. J Leukoc Biol. 2005;77(1):16–23.
    1. Murphy TJ, Paterson HM, Mannick JA, Lederer JA. Injury, sepsis, and the regulation of Toll-like receptor responses. J Leukoc Biol. 2004;75(3):400–407. doi: 10.1189/jlb.0503233.
    1. Ulloa L, Tracey KJ. The "cytokine profile": a code for sepsis. Trends Mol Med. 2005;11(2):56–63. doi: 10.1016/j.molmed.2004.12.007.
    1. Wichmann MW, Muller C, Meyer G, Adam M, Angele MK, Eisenmenger SJ, et al. Different immune responses to abdominal surgery in men and women. Langenbeck's Arch Surg. 2003;387(11-12):397–401.
    1. Majetschak M, Christensen B, Obertacke U, Waydhas C, Schindler AE, Nast-Kolb D, et al. Sex differences in posttraumatic cytokine release of endotoxin-stimulated whole blood: relationship to the development of severe sepsis. J Trauma. 2000;48(5):832–839. doi: 10.1097/00005373-200005000-00006.
    1. Oberholzer A, Keel M, Zellweger R, Steckholzer U, Trentz O, Ertel W. Incidence of septic complications and multiple organ failure in severely injured patients is sex specific. J Trauma. 2000;48(5):932–937. doi: 10.1097/00005373-200005000-00019.
    1. D'Agostino P, Milano S, Barbera C, Di Bella G, La Rosa M, Ferlazzo V, et al. Sex hormones modulate inflammatory mediators produced by macrophages. Ann N Y Acad Sci. 1999;876:426–429. doi: 10.1111/j.1749-6632.1999.tb07667.x.
    1. Hou J, Zheng WF. Effect of sex hormones on NK and ADCC activity of mice. Int J Immunopharmacol. 1988;10(1):15–22. doi: 10.1016/0192-0561(88)90145-2.
    1. McKay LI, Cidlowski JA. Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev. 1999;20(4):435–459.
    1. Rettew JA, Huet-Hudson YM, Marriott I. Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity. Biol Reprod. 2008;78(3):432–437. doi: 10.1095/biolreprod.107.063545.
    1. Su L, Sun Y, Ma F, Lu P, Huang H, Zhou J. Progesterone inhibits Toll-like receptor 4-mediated innate immune response in macrophages by suppressing NF-kappaB activation and enhancing SOCS1 expression. Immunol Lett. 2009;125(2):151–155. doi: 10.1016/j.imlet.2009.07.003.
    1. Furukawa K, Itoh K, Okamura K, Kumagai K, Suzuki M. Changes in Nk Cell-Activity during the Estrous-Cycle and Pregnancy in Mice. J Reprod Immunol. 1984;6(6):353–363. doi: 10.1016/0165-0378(84)90045-7.
    1. Lu FX, Abel K, Ma Z, Rourke T, Lu D, Torten J, et al. The strength of B cell immunity in female rhesus macaques is controlled by CD8+ T cells under the influence of ovarian steroid hormones. Clin Exp Immunol. 2002;128(1):10–20. doi: 10.1046/j.1365-2249.2002.01780.x.
    1. Miller L, Hunt JS. Sex steroid hormones and macrophage function. Life Sci. 1996;59(1):1–14. doi: 10.1016/0024-3205(96)00122-1.
    1. Savita RU. Sex steroid hormones modulate the activation of murine peritoneal macrophages: Receptor mediated modulation. Comp Biochem Physiol C. 1998;119(2):199–204.
    1. Robinson DP, Klein SL. Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav. 2012;62(3):263–271. doi: 10.1016/j.yhbeh.2012.02.023.
    1. Sorachi K, Kumagai S, Sugita M, Yodoi J, Imura H. Enhancing effect of 17 beta-estradiol on human NK cell activity. Immunol Lett. 1993;36(1):31–35. doi: 10.1016/0165-2478(93)90065-A.
    1. Kahlke V, Angele MK, Ayala A, Schwacha MG, Cioffi WG, Bland KI, et al. Immune dysfunction following trauma-haemorrhage: influence of gender and age. Cytokine. 2000;12(1):69–77. doi: 10.1006/cyto.1999.0511.
    1. Straub RH. The complex role of estrogens in inflammation. Endocr Rev. 2007;28(5):521–574. doi: 10.1210/er.2007-0001.
    1. Vegeto E, Pollio G, Pellicciari C, Maggi A. Estrogen and progesterone induction of survival of monoblastoid cells undergoing TNF-alpha-induced apoptosis. FASEB J. 1999;13(8):793–803.
    1. Ananthakrishnan P, Cohen DB, Xu DZ, Lu Q, Feketeova E, Deitch EA. Sex hormones modulate distant organ injury in both a trauma/hemorrhagic shock model and a burn model. Surgery. 2005;137(1):56–65. doi: 10.1016/j.surg.2004.04.037.
    1. Angele MK, Schwacha MG, Ayala A, Chaudry IH. Effect of gender and sex hormones on immune responses following shock. Shock. 2000;14(2):81–90. doi: 10.1097/00024382-200014020-00001.
    1. Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH. Testosterone: the culprit for producing splenocyte immune depression after trauma hemorrhage. Am J Phys. 1998;274(6 Pt 1):C1530–C1536.
    1. Angele MK, Ayala A, Monfils BA, Cioffi WG, Bland KI, Chaudry IH. Testosterone and/or low estradiol: normally required but harmful immunologically for males after trauma-hemorrhage. J Trauma. 1998;44(1):78–85. doi: 10.1097/00005373-199801000-00007.
    1. Angele MK, Knoferl MW, Ayala A, Bland KI, Chaudry IH. Testosterone and estrogen differently effect Th1 and Th2 cytokine release following trauma-haemorrhage. Cytokine. 2001;16(1):22–30. doi: 10.1006/cyto.2001.0945.
    1. Wichmann MW, Ayala A, Chaudry IH. Male sex steroids are responsible for depressing macrophage immune function after trauma-hemorrhage. Am J Phys. 1997;273(4 Pt 1):C1335–C1340.
    1. Wichmann MW, Zellweger R, DeMaso CM, Ayala A, Chaudry IH. Mechanism of immunosuppression in males following trauma-hemorrhage. Critical role of testosterone. Arch Surg. 1996;131(11):1186–1191. doi: 10.1001/archsurg.1996.01430230068012.
    1. Knoferl MW, Angele MK, Schwacha MG, Bland KI, Chaudry IH. Preservation of splenic immune functions by female sex hormones after trauma-hemorrhage. Crit Care Med. 2002;30(4):888–893. doi: 10.1097/00003246-200204000-00029.
    1. Knoferl MW, Diodato MD, Angele MK, Ayala A, Cioffi WG, Bland KI, et al. Do female sex steroids adversely or beneficially affect the depressed immune responses in males after trauma-hemorrhage? Arch Surg. 2000;135(4):425–433. doi: 10.1001/archsurg.135.4.425.
    1. Knoferl MW, Jarrar D, Angele MK, Ayala A, Schwacha MG, Bland KI, et al. 17 beta-Estradiol normalizes immune responses in ovariectomized females after trauma-hemorrhage. Am J Phys Cell Physiol. 2001;281(4):C1131–C1138.
    1. Dienstknecht T, Schwacha MG, Kang SC, Rue LW, Bland KI, Chaudry IH. Sex steroid-mediated regulation of macrophage/monocyte function in a two-hit model of trauma-hemorrhage and sepsis. Cytokine. 2004;25(3):110–118. doi: 10.1016/j.cyto.2003.10.006.
    1. Mayr S, Walz CR, Angele P, Hernandez-Richter T, Chaudry IH, Loehe F, et al. Castration prevents suppression of MHC class II (Ia) expression on macrophages after trauma-hemorrhage. J Appl Physiol (1985) 2006;101(2):448–453. doi: 10.1152/japplphysiol.00166.2006.
    1. Hildebrand F, Hubbard WJ, Choudhry MA, Thobe BM, Pape HC, Chaudry IH. Are the protective effects of 17beta-estradiol on splenic macrophages and splenocytes after trauma-hemorrhage mediated via estrogen-receptor (ER)-alpha or ER-beta? J Leukoc Biol. 2006;79(6):1173–1180. doi: 10.1189/jlb.0106029.
    1. Samy TS, Zheng R, Matsutani T, Rue LW, 3rd, Bland KI, Chaudry IH. Mechanism for normal splenic T lymphocyte functions in proestrus females after trauma: enhanced local synthesis of 17beta-estradiol. Am J Phys Cell Physiol. 2003;285(1):C139–C149. doi: 10.1152/ajpcell.00058.2003.
    1. Suzuki T, Shimizu T, Yu HP, Hsieh YC, Choudhry MA, Bland KI, et al. Estrogen receptor-alpha predominantly mediates the salutary effects of 17beta-estradiol on splenic macrophages following trauma-hemorrhage. Am J Phys Cell Physiol. 2007;293(3):C978–C984. doi: 10.1152/ajpcell.00092.2007.
    1. Kawasaki T, Choudhry MA, Suzuki T, Schwacha MG, Bland KI, Chaudry IH. 17beta-Estradiol's salutary effects on splenic dendritic cell functions following trauma-hemorrhage are mediated via estrogen receptor-alpha. Mol Immunol. 2008;45(2):376–385. doi: 10.1016/j.molimm.2007.06.148.
    1. Trentzsch H, Nienaber U, Behnke M, Lefering R, Piltz S. Female sex protects from organ failure and sepsis after major trauma haemorrhage. Injury. 2014;45(Suppl 3):S20–S28. doi: 10.1016/j.injury.2014.08.013.
    1. Zolin SJ, Vodovotz Y, Forsythe RM, Rosengart MR, Namas R, Brown JB, et al. The early evolving sex hormone environment is associated with significant outcome and inflammatory response differences after injury. J Trauma Acute Care Surg. 2015;78(3):451–457. doi: 10.1097/TA.0000000000000550.
    1. Gee AC, Sawai RS, Differding J, Muller P, Underwood S, Schreiber MA. The influence of sex hormones on coagulation and inflammation in the trauma patient. Shock. 2008;29(3):334–341.
    1. Lopez MC, Efron PA, Ozrazgat-Baslanti T, Zhang J, Cuschieri J, Maier RV, et al. Sex-based differences in the genomic response, innate immunity, organ dysfunction, and clinical outcomes after severe blunt traumatic injury and hemorrhagic shock. J Trauma Acute Care Surg. 2016;81(3):478–485. doi: 10.1097/TA.0000000000001113.
    1. Wang P, Ba ZF, Burkhardt J, Chaudry IH. Trauma-hemorrhage and resuscitation in the mouse: effects on cardiac output and organ blood flow. Am J Phys. 1993;264(4 Pt 2):H1166–H1173.
    1. Wang P, Hauptman JG, Chaudry IH. Hemorrhage produces depression in microvascular blood flow which persists despite fluid resuscitation. Circ Shock. 1990;32(4):307–318.
    1. Remmers DE, Cioffi WG, Bland KI, Wang P, Angele MK, Chaudry IH. Testosterone: the crucial hormone responsible for depressing myocardial function in males after trauma-hemorrhage. Ann Surg. 1998;227(6):790–799. doi: 10.1097/00000658-199806000-00002.
    1. Remmers DE, Wang P, Cioffi WG, Bland KI, Chaudry IH. Testosterone receptor blockade after trauma-hemorrhage improves cardiac and hepatic functions in males. Am J Phys. 1997;273(6 Pt 2):H2919–H2925.
    1. Kuebler JF, Jarrar D, Bland KI, Rue L, 3rd, Wang P, Chaudry IH. Progesterone administration after trauma and hemorrhagic shock improves cardiovascular responses. Crit Care Med. 2003;31(6):1786–1793. doi: 10.1097/01.CCM.0000063441.41446.23.
    1. Jarrar D, Wang P, Cioffi WG, Bland KI, Chaudry IH. The female reproductive cycle is an important variable in the response to trauma-hemorrhage. Am J Physiol Heart Circ Physiol. 2000;279(3):H1015–H1021.
    1. Mizushima Y, Wang P, Jarrar D, Cioffi WG, Bland KI, Chaudry IH. Estradiol administration after trauma-hemorrhage improves cardiovascular and hepatocellular functions in male animals. Ann Surg. 2000;232(5):673–679. doi: 10.1097/00000658-200011000-00009.
    1. Nickel EA, Hsieh CH, Chen JG, Schwacha MG, Chaudry IH. Estrogen suppresses cardiac IL-6 after trauma-hemorrhage via a hypoxia-inducible factor 1 alpha-mediated pathway. Shock. 2009;31(4):354–358. doi: 10.1097/SHK.0b013e3181862fdd.
    1. Yang S, Zheng R, Hu S, Ma Y, Choudhry MA, Messina JL, et al. Mechanism of cardiac depression after trauma-hemorrhage: increased cardiomyocyte IL-6 and effect of sex steroids on IL-6 regulation and cardiac function. Am J Physiol Heart Circ Physiol. 2004;287(5):H2183–H2191. doi: 10.1152/ajpheart.00624.2003.
    1. Szalay L, Shimizu T, Schwacha MG, Choudhry MA, Rue LW, 3rd, Bland KI, et al. Mechanism of salutary effects of estradiol on organ function after trauma-hemorrhage: upregulation of heme oxygenase. Am J Physiol Heart Circ Physiol. 2005;289(1):H92–H98. doi: 10.1152/ajpheart.01247.2004.
    1. Hsu JT, Hsieh YC, Kan WH, Chen JG, Choudhry MA, Schwacha MG, et al. Role of p38 mitogen-activated protein kinase pathway in estrogen-mediated cardioprotection following trauma-hemorrhage. Am J Physiol Heart Circ Physiol. 2007;292(6):H2982–H2987. doi: 10.1152/ajpheart.01303.2006.
    1. Kan WH, Hsu JT, Ba ZF, Schwacha MG, Chen J, Choudhry MA, et al. p38 MAPK-dependent eNOS upregulation is critical for 17beta-estradiol-mediated cardioprotection following trauma-hemorrhage. Am J Physiol Heart Circ Physiol. 2008;294(6):H2627–H2636. doi: 10.1152/ajpheart.91444.2007.
    1. Hsu JT, Kan WH, Hsieh CH, Choudhry MA, Bland KI, Chaudry IH. Mechanism of salutary effects of estrogen on cardiac function following trauma-hemorrhage: Akt-dependent HO-1 up-regulation. Crit Care Med. 2009;37(8):2338–2344. doi: 10.1097/CCM.0b013e3181a030ce.
    1. Liu CJ, Lo JF, Kuo CH, Chu CH, Chen LM, Tsai FJ, et al. Akt mediates 17beta-estradiol and/or estrogen receptor-alpha inhibition of LPS-induced tumor necresis factor-alpha expression and myocardial cell apoptosis by suppressing the JNK1/2-NFkappaB pathway. J Cell Mol Med. 2009;13(9b):3655–3667. doi: 10.1111/j.1582-4934.2009.00669.x.
    1. Yu HP, Hsieh YC, Suzuki T, Choudhry MA, Schwacha MG, Bland KI, et al. The PI3K/Akt pathway mediates the nongenomic cardioprotective effects of estrogen following trauma-hemorrhage. Ann Surg. 2007;245(6):971–977. doi: 10.1097/01.sla.0000254417.15591.88.
    1. Wang M, Wang Y, Abarbanell A, Tan J, Weil B, Herrmann J, et al. Both Endogenous And Exogenous Testosterone Decrease Myocardial Stat3 Activation And Socs3 Expression Following Acute Ischemia And Reperfusion. Surgery. 2009;146(2):138–144. doi: 10.1016/j.surg.2009.03.035.
    1. Huang C, Gu H, Zhang W, Herrmann JL, Wang M. Testosterone-down-regulated Akt pathway during cardiac ischemia/reperfusion: a mechanism involving BAD, Bcl-2 and FOXO3a. J Surg Res. 2010;164(1):e1–11. doi: 10.1016/j.jss.2010.07.041.
    1. Pongkan W, Chattipakorn SC, Chattipakorn N. Roles of Testosterone Replacement in Cardiac Ischemia-Reperfusion Injury. J Cardiovasc Pharmacol Ther. 2016;21(1):27–43. doi: 10.1177/1074248415587977.
    1. Koh KK, Mincemoyer R, Bui MN, Csako G, Pucino F, Guetta V, et al. Effects of Hormone-Replacement Therapy on Fibrinolysis in Postmenopausal Women. N Engl J Med. 1997;336(10):683–691. doi: 10.1056/NEJM199703063361002.
    1. Harnett MJ, Bhavani-Shankar K, Datta S, Tsen LC. In vitro fertilization-induced alterations in coagulation and fibrinolysis as measured by thromboelastography. Anesth Analg. 2002;95(4):1063–1066.
    1. Schreiber MA, Differding J, Thorborg P, Mayberry JC, Mullins RJ. Hypercoagulability is most prevalent early after injury and in female patients. J Trauma. 2005;58(3):475–480. doi: 10.1097/01.TA.0000153938.77777.26.
    1. Brown JB, Cohen MJ, Minei JP, Maier RV, West MA, Billiar TR, et al. Characterization of acute coagulopathy and sexual dimorphism after injury: females and coagulopathy just do not mix. J Trauma Acute Care Surg. 2012;73(6):1395–1400. doi: 10.1097/TA.0b013e31825b9f05.
    1. Erikoglu M, Sahin M, Ozer S, Avunduk MC. Effects of gender on the severity of sepsis. Surg Today. 2005;35(6):467–472. doi: 10.1007/s00595-004-2958-3.
    1. Eckhoff DE, Bilbao G, Frenette L, Thompson JA, Contreras JL. 17-Beta-estradiol protects the liver against warm ischemia/reperfusion injury and is associated with increased serum nitric oxide and decreased tumor necrosis factor-alpha. Surgery. 2002;132(2):302–309. doi: 10.1067/msy.2002.125718.
    1. Hsieh CH, Nickel EA, Chen J, Schwacha MG, Choudhry MA, Bland KI, et al. Mechanism of the salutary effects of estrogen on kupffer cell phagocytic capacity following trauma-hemorrhage: pivotal role of Akt activation. J Immunol. 2009;182(7):4406–4414. doi: 10.4049/jimmunol.0803423.
    1. Hsieh YC, Frink M, Thobe BM, Hsu JT, Choudhry MA, Schwacha MG, et al. 17Beta-estradiol downregulates Kupffer cell TLR4-dependent p38 MAPK pathway and normalizes inflammatory cytokine production following trauma-hemorrhage. Mol Immunol. 2007;44(9):2165–2172. doi: 10.1016/j.molimm.2006.11.019.
    1. Yokoyama Y, Kuebler JF, Matsutani T, Schwacha MG, Bland KI, Chaudry IH. Mechanism of the salutary effects of 17beta-estradiol following trauma-hemorrhage: direct downregulation of Kupffer cell proinflammatory cytokine production. Cytokine. 2003;21(2):91–97. doi: 10.1016/S1043-4666(03)00014-0.
    1. Hsieh YC, Frink M, Kawasaki T, Thobe BM, Choudhry MA, Schwacha MG, et al. Downregulation of TLR4-dependent ATP production is critical for estrogen-mediated immunoprotection in Kupffer cells following trauma-hemorrhage. J Cell Physiol. 2007;211(2):364–370. doi: 10.1002/jcp.20943.
    1. Hsu JT, Kan WH, Hsieh CH, Choudhry MA, Schwacha MG, Bland KI, et al. Mechanism of estrogen-mediated attenuation of hepatic injury following trauma-hemorrhage: Akt-dependent HO-1 up-regulation. J Leukoc Biol. 2007;82(4):1019–1026. doi: 10.1189/jlb.0607355.
    1. Yang S, Hu S, Chen J, Choudhry MA, Rue LW, 3rd, Bland KI, et al. Mechanism of hepatoprotection in proestrus female rats following trauma-hemorrhage: heme oxygenase-1-derived normalization of hepatic inflammatory responses. J Leukoc Biol. 2009;85(6):1015–1026. doi: 10.1189/jlb.0508288.
    1. Suzuki T, Shimizu T, Yu HP, Hsieh YC, Choudhry MA, Bland KI, et al. 17 beta-estradiol administration following trauma-hemorrhage prevents the increase in Kupffer cell cytokine production and MAPK activation predominately via estrogen receptor-alpha. Surgery. 2006;140(2):141–148. doi: 10.1016/j.surg.2006.02.014.
    1. Han JE, Jones JL, Tangpricha V, Brown MA, Brown LA, Hao L, et al. High Dose Vitamin D Administration in Ventilated Intensive Care Unit Patients: A Pilot Double Blind Randomized Controlled Trial. J Clin Transl Endocrinol. 2016;4:59–65. doi: 10.1016/j.jcte.2016.04.004.
    1. Hsieh YC, Yu HP, Frink M, Suzuki T, Choudhry MA, Schwacha MG, et al. G protein-coupled receptor 30-dependent protein kinase A pathway is critical in nongenomic effects of estrogen in attenuating liver injury after trauma-hemorrhage. Am J Pathol. 2007;170(4):1210–1218. doi: 10.2353/ajpath.2007.060883.
    1. Sheth SU, Palange D, Xu DZ, Wei D, Feketeova E, Lu Q, et al. Testosterone depletion or blockade in male rats protects against trauma hemorrhagic shock-induced distant organ injury by limiting gut injury and subsequent production of biologically active mesenteric lymph. J Trauma. 2011;71(6):1652–1658.
    1. Deitch EA, Senthil M, Brown M, Caputo F, Watkins A, Anjaria D, et al. Trauma-shock-induced gut injury and the production of biologically active intestinal lymph is abrogated by castration in a large animal porcine model. Shock. 2008;30(2):135–141.
    1. Ba ZF, Shimizu T, Szalay L, Bland KI, Chaudry IH. Gender differences in small intestinal perfusion following trauma hemorrhage: the role of endothelin-1. Am J Physiol Gastrointest Liver Physiol. 2005;288(5):G860–G865. doi: 10.1152/ajpgi.00437.2004.
    1. Yokoyama Y, Toth B, Kitchens WC, Schwacha MG, Rue LW, 3rd, Bland KI, et al. Estradiol's effect on portal response to endothelin-1 after trauma-hemorrhage. J Surg Res. 2004;121(1):25–30. doi: 10.1016/j.jss.2004.03.012.
    1. Hsu JT, Kan WH, Hsieh CH, Choudhry MA, Schwacha MG, Bland KI, et al. Mechanism of estrogen-mediated intestinal protection following trauma-hemorrhage: p38 MAPK-dependent upregulation of HO-1. Am J Phys Regul Integr Comp Phys. 2008;294(6):R1825–R1831.
    1. Yu HP, Hsieh YC, Suzuki T, Choudhry MA, Schwacha MG, Bland KI, et al. Mechanism of the nongenomic effects of estrogen on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of the PI-3K/Akt pathway. J Leukoc Biol. 2007;82(3):774–780. doi: 10.1189/jlb.0307182.
    1. Shimizu T, Yu HP, Hsieh YC, Choudhry MA, Suzuki T, Bland KI, et al. Flutamide attenuates pro-inflammatory cytokine production and hepatic injury following trauma-hemorrhage via estrogen receptor-related pathway. Ann Surg. 2007;245(2):297–304. doi: 10.1097/01.sla.0000232523.88621.17.
    1. Caruso JM, Xu DZ, Lu Q, Dayal SD, Deitch EA. The female gender protects against pulmonary injury after trauma hemorrhagic shock. Surg Infect. 2001;2(3):231–240. doi: 10.1089/109629601317202713.
    1. Tominaga K, Kataoka Y, Sendo T, Furuta W, Niizeki M, Oishi AR. Contrast medium-induced pulmonary vascular hyperpermeability is aggravated in a rat climacterium model. Investig Radiol. 2001;36(3):131–135. doi: 10.1097/00004424-200103000-00001.
    1. Frink M, Thobe BM, Hsieh YC, Choudhry MA, Schwacha MG, Bland KI, et al. 17beta-Estradiol inhibits keratinocyte-derived chemokine production following trauma-hemorrhage. Am J Phys Lung Cell Mol Phys. 2007;292(2):L585–L591.
    1. Hsieh YC, Frink M, Hsieh CH, Choudhry MA, Schwacha MG, Bland KI, et al. Downregulation of migration inhibitory factor is critical for estrogen-mediated attenuation of lung tissue damage following trauma-hemorrhage. Am J Phys Lung Cell Mol Phys. 2007;292(5):L1227–L1232.
    1. Hsu JT, Kan WH, Hsieh CH, Choudhry MA, Bland KI, Chaudry IH. Role of extracellular signal-regulated protein kinase (ERK) in 17beta-estradiol-mediated attenuation of lung injury after trauma-hemorrhage. Surgery. 2009;145(2):226–234. doi: 10.1016/j.surg.2008.10.008.
    1. Kan WH, Hsu JT, Schwacha MG, Choudhry MA, Bland KI, Chaudry IH. Estrogen ameliorates trauma-hemorrhage-induced lung injury via endothelial nitric oxide synthase-dependent activation of protein kinase G. Ann Surg. 2008;248(2):294–302. doi: 10.1097/SLA.0b013e318180a3db.
    1. Chisari AN, Gaillard RC, Giovambattista A, Voirol MJ, Piermaria J, Spinedi E. Sexual dimorphism in the hypothalamo-pituitary-adrenal (HPA) axis and TNFalpha responses to phospholipase A2-related neurotoxin (from crotalus durissus terrifcus) challenge. J Endocrinol Investig. 2000;23(7):440–448. doi: 10.1007/BF03343753.
    1. Regan RF, Guo Y. Estrogens attenuate neuronal injury due to hemoglobin, chemical hypoxia, and excitatory amino acids in murine cortical cultures. Brain Res. 1997;764(1-2):133–140. doi: 10.1016/S0006-8993(97)00437-X.
    1. Coughlan T, Gibson C, Murphy S. Modulatory effects of progesterone on inducible nitric oxide synthase expression in vivo and in vitro. J Neurochem. 2005;93(4):932–942. doi: 10.1111/j.1471-4159.2005.03068.x.
    1. Lin CL, Shih HC, Dumont AS, Kassell NF, Lieu AS, Su YF, et al. The effect of 17beta-estradiol in attenuating experimental subarachnoid hemorrhage-induced cerebral vasospasm. J Neurosurg. 2006;104(2):298–304. doi: 10.3171/jns.2006.104.2.298.
    1. Akabori H, Moeinpour F, Bland KI, Chaudry IH. Mechanism of the anti-inflammatory effect Of 17beta-estradiol on brain following trauma-hemorrhage. Shock. 2010;33(1):43–48. doi: 10.1097/SHK.0b013e3181b0ebcb.
    1. Liu R, Wen Y, Perez E, Wang X, Day AL, Simpkins JW, et al. 17beta-Estradiol attenuates blood-brain barrier disruption induced by cerebral ischemia-reperfusion injury in female rats. Brain Res. 2005;1060(1-2):55–61. doi: 10.1016/j.brainres.2005.08.048.
    1. Hall ED, Pazara KE, Linseman KL. Sex differences in postischemic neuronal necrosis in gerbils. J Cereb Blood Flow Metab. 1991;11(2):292–298. doi: 10.1038/jcbfm.1991.61.
    1. Fantappie MR, Galina A, Luis de Mendonca R, Furtado DR, Secor WE, Colley DG, et al. Molecular characterisation of a NADH ubiquinone oxidoreductase subunit 5 from Schistosoma mansoni and inhibition of mitochondrial respiratory chain function by testosterone. Mol Cell Biochem. 1999;202(1-2):149–158. doi: 10.1023/A:1007057903390.
    1. Wagner AK, McCullough EH, Niyonkuru C, Ozawa H, Loucks TL, Dobos JA, et al. Acute serum hormone levels: characterization and prognosis after severe traumatic brain injury. J Neurotrauma. 2011;28(6):871–888. doi: 10.1089/neu.2010.1586.
    1. Gurer B, Kertmen H, Kasim E, Yilmaz ER, Kanat BH, Sargon MF, et al. Neuroprotective effects of testosterone on ischemia/reperfusion injury of the rabbit spinal cord. Injury. 2015;46(2):240–248. doi: 10.1016/j.injury.2014.11.002.
    1. Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, MacAllister T, Ward JD, et al. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med. 2014;371(26):2467–2476. doi: 10.1056/NEJMoa1411090.
    1. Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, et al. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med. 2014;371(26):2457–2466. doi: 10.1056/NEJMoa1404304.
    1. Lin C, He H, Li Z, Liu Y, Chao H, Ji J, et al. Efficacy of progesterone for moderate to severe traumatic brain injury: a meta-analysis of randomized clinical trials. Sci Rep. 2015;5:13442. doi: 10.1038/srep13442.
    1. Ma J, Huang S, Qin S, You C, Zeng Y. Progesterone for acute traumatic brain injury. Cochrane Database Syst Rev. 2016;12:Cd008409.
    1. Park KM, Kim JI, Ahn Y, Bonventre AJ, Bonventre JV. Testosterone is responsible for enhanced susceptibility of males to ischemic renal injury. J Biol Chem. 2004;279(50):52282–52292. doi: 10.1074/jbc.M407629200.
    1. Patil CN, Wallace K, LaMarca BD, Moulana M, Lopez-Ruiz A, Soljancic A, et al. Low-dose testosterone protects against renal ischemia-reperfusion injury by increasing renal IL-10-to-TNF-alpha ratio and attenuating T-cell infiltration. Am J Physiol Ren Physiol. 2016;311(2):F395–F403. doi: 10.1152/ajprenal.00454.2015.
    1. Satake A, Takaoka M, Nishikawa M, Yuba M, Shibata Y, Okumura K, et al. Protective effect of 17beta-estradiol on ischemic acute renal failure through the PI3K/Akt/eNOS pathway. Kidney Int. 2008;73(3):308–317. doi: 10.1038/sj.ki.5002690.
    1. Kasimay O, Sener G, Cakir B, Yuksel M, Cetinel S, Contuk G, et al. Estrogen protects against oxidative multiorgan damage in rats with chronic renal failure. Ren Fail. 2009;31(8):711–725. doi: 10.3109/08860220903134563.
    1. Pereira CT, Murphy KD, Herndon DN. Altering metabolism. J Burn Care Rehabil. 2005;26(3):194–199.
    1. Jeschke MG, Chinkes DL, Finnerty CC, Kulp G, Suman OE, Norbury WB, et al. Pathophysiologic response to severe burn injury. Ann Surg. 2008;248(3):387–401.
    1. Milner EA, Cioffi WG, Mason AD, McManus WF, Pruitt BA., Jr A longitudinal study of resting energy expenditure in thermally injured patients. J Trauma. 1994;37(2):167–170. doi: 10.1097/00005373-199408000-00001.
    1. Wolfe RR. Metabolic response to burn injury: nutritional implications. Keio J Med. 1993;42(1):1–8. doi: 10.2302/kjm.42.1.
    1. Tredget EE, Yu YM. The metabolic effects of thermal injury. World J Surg. 1992;16(1):68–79. doi: 10.1007/BF02067117.
    1. Hampson P, Dinsdale RJ, Wearn CM, Bamford AL, Bishop JRB, Hazeldine J, et al. Neutrophil Dysfunction, Immature Granulocytes, and Cell-free DNA are Early Biomarkers of Sepsis in Burn-injured Patients: A Prospective Observational Cohort Study. Ann Surg. 2017;265(6):1241–1249. doi: 10.1097/SLA.0000000000001807.
    1. Porter C, Tompkins RG, Finnerty CC, Sidossis LS, Suman OE, Herndon DN. The metabolic stress response to burn trauma: current understanding and therapies. Lancet. 2016;388(10052):1417–1426. doi: 10.1016/S0140-6736(16)31469-6.
    1. Chao T, Herndon DN, Porter C, Chondronikola M, Chaidemenou A, Abdelrahman DR, et al. Skeletal Muscle Protein Breakdown Remains Elevated In Pediatric Burn Survivors Up To One-Year Post-Injury. Shock. 2015;44(5):397–401. doi: 10.1097/SHK.0000000000000454.
    1. Klein GL, Herndon DN, Langman CB, Rutan TC, Young WE, Pembleton G, et al. Long-term reduction in bone mass after severe burn injury in children. J Pediatr. 1995;126(2):252–256. doi: 10.1016/S0022-3476(95)70553-8.
    1. Przkora R, Barrow RE, Jeschke MG, Suman OE, Celis M, Sanford AP, et al. Body composition changes with time in pediatric burn patients. J Trauma. 2006;60(5):968–971. doi: 10.1097/01.ta.0000214580.27501.19.
    1. Rutan RL, Herndon DN. Growth delay in postburn pediatric patients. Arch Surg. 1990;125(3):392–395. doi: 10.1001/archsurg.1990.01410150114021.
    1. Jeschke MG, Gauglitz GG, Kulp GA, Finnerty CC, Williams FN, Kraft R, et al. Long-term persistance of the pathophysiologic response to severe burn injury. PLoS One. 2011;6(7):e21245. doi: 10.1371/journal.pone.0021245.
    1. Hussain A, Dunn K. Burn related mortality in Greater Manchester: 11-year review of Regional Coronial Department Data. Burns. 2015;41(2):225–234. doi: 10.1016/j.burns.2014.10.008.
    1. Stylianou N, Buchan I, Dunn KW. A review of the international Burn Injury Database (iBID) for England and Wales: descriptive analysis of burn injuries 2003-2011. BMJ Open. 2015;5(2):e006184. doi: 10.1136/bmjopen-2014-006184.
    1. Summers JI, Ziembicki JA, Corcos AC, Peitzman AB, Billiar TR, Sperry JL. Characterization of sex dimorphism following severe thermal injury. J Burn Care Res. 2014;35(6):484–490. doi: 10.1097/BCR.0000000000000018.
    1. Lawrence JW, Mason ST, Schomer K, Klein MB. Epidemiology and impact of scarring after burn injury: a systematic review of the literature. J Burn Care Res. 2012;33(1):136–146. doi: 10.1097/BCR.0b013e3182374452.
    1. Wigginton JG, Pepe PE, Idris AH. Rationale for routine and immediate administration of intravenous estrogen for all critically ill and injured patients. Crit Care Med. 2010;38(10 Suppl):S620–S629. doi: 10.1097/CCM.0b013e3181f243a9.
    1. Abdelfattah KR, Gatson JW, Maass DL, Wolf SE, Minei JP, Wigginton JG. 17beta-Estradiol reappropriates mass lost to the hypermetabolic state in thermally injured rats. J Surg Res. 2013;181(1):136–141. doi: 10.1016/j.jss.2012.06.010.
    1. Gregory MS, Duffner LA, Faunce DE, Kovacs EJ. Estrogen mediates the sex difference in post-burn immunosuppression. J Endocrinol. 2000;164(2):129–138. doi: 10.1677/joe.0.1640129.
    1. Gatson JW, Maass DL, Simpkins JW, Idris AH, Minei JP, Wigginton JG. Estrogen treatment following severe burn injury reduces brain inflammation and apoptotic signaling. J Neuroinflammation. 2009;6:30. doi: 10.1186/1742-2094-6-30.
    1. Ozveri ES, Bozkurt A, Haklar G, Cetinel S, Arbak S, Yegen C, et al. Estrogens ameliorate remote organ inflammation induced by burn injury in rats. Inflamm Res. 2001;50(12):585–591. doi: 10.1007/PL00000238.
    1. Kuhn CM. Anabolic steroids. Recent Prog Horm Res. 2002;57:411–434. doi: 10.1210/rp.57.1.411.
    1. Orr R, Fiatarone SM. The anabolic androgenic steroid oxandrolone in the treatment of wasting and catabolic disorders: review of efficacy and safety. Drugs. 2004;64(7):725–750. doi: 10.2165/00003495-200464070-00004.
    1. Wolf SE, Edelman LS, Kemalyan N, Donison L, Cross J, Underwood M, et al. Effects of oxandrolone on outcome measures in the severely burned: a multicenter prospective randomized double-blind trial. J Burn Care Res. 2006;27(2):131–139. doi: 10.1097/01.BCR.0000202620.55751.4F.
    1. Li H, Guo Y, Yang Z, Roy M, Guo Q. The efficacy and safety of oxandrolone treatment for patients with severe burns: A systematic review and meta-analysis. Burns. 2016;42(4):717–727. doi: 10.1016/j.burns.2015.08.023.
    1. Herndon DN, Voigt CD, Capek KD, Wurzer P, Guillory A, Kline A, et al. Reversal of Growth Arrest With the Combined Administration of Oxandrolone and Propranolol in Severely Burned Children. Ann Surg. 2016;264(3):421–428. doi: 10.1097/SLA.0000000000001844.
    1. Reeves PT, Herndon DN, Tanksley JD, Jennings K, Klein GL, Mlcak RP, et al. Five-Year Outcomes After Long-Term Oxandrolone Administration In Severely Burned Children: A Randomized Clinical Trial. Shock. 2016;45(4):367–374. doi: 10.1097/SHK.0000000000000517.
    1. Ebeling P, Koivisto VA. Physiological importance of dehydroepiandrosterone. Lancet. 1994;343(8911):1479–81.
    1. Angele MK, Catania RA, Ayala A, Cioffi WG, Bland KI, Chaudry IH. Dehydroepiandrosterone: an inexpensive steroid hormone that decreases the mortality due to sepsis following trauma-induced hemorrhage. Arch Surg. 1998;133(12):1281–8.
    1. Catania RA, Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH. Dehydroepiandrosterone restores immune function following trauma-haemorrhage by a direct effect on T lymphocytes. Cytokine. 1999;11(6):443–50.
    1. Blauer KL, Poth M, Rogers WM, Bernton EW. Dehydroepiandrosterone antagonizes the suppressive effects of dexamethasone on lymphocyte proliferation. Endocrinology. 1991;129(6):3174–9.
    1. Radford DJ, Wang K, McNelis JC, Taylor AE, Hechenberger G, Hofmann J, et al. Dehydroepiandrosterone sulfate directly activates protein kinase C-beta to increase human neutrophil superoxide generation. Mol Endocrinol. 2010;24(4):813–21.
    1. Wichmann MW, Angele MK, Ayala A, Cioffi WG, Chaudry IH. Flutamide: a novel agent for restoring the depressed cell-mediated immunity following soft-tissue trauma and hemorrhagic shock. Shock. 1997;8(4):242–248. doi: 10.1097/00024382-199710000-00002.
    1. Angele MK, Wichmann MW, Ayala A, Cioffi WG, Chaudry IH. Testosterone receptor blockade after hemorrhage in males. Restoration of the depressed immune functions and improved survival following subsequent sepsis. Arch Surg. 1997;132(11):1207–14.
    1. Lin CY, Hsu CC, Lin MT, Chen SH. Flutamide, an androgen receptor antagonist, improves heatstroke outcomes in mice. Eur J Pharmacol. 2012;688(1-3):62–7.

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