Estradiol to Androstenedione Ratios Moderate the Relationship between Neurological Injury Severity and Mortality Risk after Severe Traumatic Brain Injury
Restricted accessResearch articleFirst published online February, 2019
Estradiol to Androstenedione Ratios Moderate the Relationship between Neurological Injury Severity and Mortality Risk after Severe Traumatic Brain Injury
Early declines in gonadotropin production, despite elevated serum estradiol, among some individuals with severe traumatic brain injury (TBI) suggests amplified systemic aromatization occurs post-injury. Our previous work identifies estradiol (E2) as a potent mortality marker. Androstenedione (A), a metabolic precursor to E2, estrone (E1), and testosterone (T), is a steroid hormone substrate for aromatization that has not been explored previously as a biomarker in TBI. Here, we evaluated serum A, E1, T, and E2 values for 82 subjects with severe TBI. Daily hormone values were calculated, and E2:A and E1:T ratios were generated and then averaged for days 0–3 post-injury. After data inspection, mean E2:A values were categorized as above (high aromatization) and below (low aromatization) the 50th percentile for 30-day mortality assessment using Kaplan-Meier survival analysis and a multivariable Cox proportional hazard model adjusting for age, and Glasgow Coma Scale (GCS) to predict 30-day mortality status. Daily serum T, E1, and E2 were graphed by E2:A category. Serum E1 and E2 significantly differed over time (p < 0.05); the high aromatization group had elevated levels and a significantly lower probability of survival within the first 30 days (p = 0.0274). Multivariable Cox regression showed a significant E2:A*GCS interaction (p = 0.0129), wherein GCS predicted mortality only among those in the low aromatization group. E2:A may be a useful mortality biomarker representing enhanced aromatization after TBI. E2:A ratios may represent non-neurological organ dysfunction after TBI and may be useful in defining injury subgroups in which GCS has variable capacity to serve as an accurate early prognostic marker.
Get full access to this article
View all access options for this article.
References
1.
Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006 (Blue Book) | Concussion | Traumatic Brain Injury | CDC Injury Center. (2010). Centers for Disease Control and Prevention. Available at: www.cdc.gov/traumaticbraininjury/tbi_ed.html. Last accessed Auust 12, 2018.
2.
RoozenbeekB., MaasA.I., and MenonD.K. (2013). Changing patterns in the epidemiology of traumatic brain injury. Nat. Rev. Neurol., 9, 231–236.
3.
CorralL., JavierreC.F., VenturaJ.L., MarcosP., HerreroJ.I., and MañezR. (2012). Impact of non-neurological complications in severe traumatic brain injury outcome. Crit. Care, 16, R44.
4.
KempC.D., JohnsonJ.C., RiordanW.P., and CottonB.A. (2008). How we die: the impact of nonneurologic organ dysfunction after severe traumatic brain injury. Am. Surg., 74, 866–872.
5.
LeyE.J., ClondM.A., BukurM., ParkR., ChervonskiM., DagliyanG., MarguliesD.R., LydenP.D., ContiP.S., and SalimA. (2012). β-adrenergic receptor inhibition affects cerebral glucose metabolism, motor performance, and inflammatory response after traumatic brain injury. J. Trauma Acute Care Surg., 73, 33–40.
6.
AnthonyD.C., and CouchY. (2014). The systemic response to CNS injury. Exp. Neurol., 258, 105–111.
7.
NanceD.M., and SandersV.M. (2007). Autonomic innervation and regulation of the immune system (1987–2007). Brain. Behav. Immun., 21, 736–745.
8.
ElenkovI.J., WilderR.L., ChrousosG.P., and ViziE.S. (2000). The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol. Rev., 52, 595–638.
9.
KenneyM.J., and GantaC.K. (2014). Autonomic nervous system and immune system interactions. Compr. Physiol., 4, 1177–1200.
PedersenA.L., NelsonL.H., and SaldanhaC.J. (2016). Centrally synthesized estradiol is a potent anti-inflammatory in the injured zebra finch brain. Endocrinology, 157, 2041–2051.
12.
LiJ., LiW.Q., and YaoY. (2016). Vasorelaxation effect of estrone derivate EA204 in rabbit aorta. Scientifica, 2016, 7405797.
13.
MontenegroM.F., CeronC.S., SalgadoM.C.O., DestaZ., FlockhartD.A., and Tanus-SantosJ.E. (2011). Tamoxifen and its metabolites cause acute vasorelaxation of aortic rings by inducing vasodilator prostanoid synthesis. J. Cardiovasc. Pharmacol., 58, 647–653.
14.
Tep-areenanP., KendallD.A., and RandallM.D. (2003). Mechanisms of vasorelaxation to 17beta-oestradiol in rat arteries. Eur. J. Pharmacol., 476, 139–149.
GarbánH.J., BugaG.M., and IgnarroL.J. (2004). Estrogen receptor-mediated vascular responsiveness to nebivolol: a novel endothelium-related mechanism of therapeutic vasorelaxation. J. Cardiovasc. Pharmacol., 43, 638–644.
17.
EgamiR., TanakaY., NozakiM., KoeraK., OkumaA., and NakanoH. (2005). Chronic treatment with 17beta-estradiol increases susceptibility of smooth muscle cells to nitric oxide. Eur. J. Pharmacol., 520, 142–149.
18.
CauwelsA., and BrouckaertP. (2011). Nitrite regulation of shock. Cardiovasc. Res., 89, 553–559.
19.
GroeneveldA.B., HarteminkK.J., de GrootM.C., VisserJ., and ThijsL.G. (1999). Circulating endothelin and nitrate-nitrite relate to hemodynamic and metabolic variables in human septic shock. Shock, 11, 160–166.
20.
SimperD., StrobelW.M., LinderL., and HaefeliW.E. (1995). Indirect evidence for stimulation of nitric oxide release by tumour necrosis factor-alpha in human veins in vivo. Cardiovasc. Res., 30, 960–964.
21.
TraceyK.J., and CeramiA. (1992). Tumor necrosis factor and regulation of metabolism in infection: role of systemic versus tissue levels. Proc. Soc. Exp. Biol. Med. Soc. Exp. Biol. Med., 200, 233–239.
22.
TraceyK.J., and CeramiA. (1993). Tumor necrosis factor: an updated review of its biology. Crit. Care Med., 21, Suppl 10, S415–S422.
23.
GarringerJ.A., NiyonkuruC., McCulloughE.H., LoucksT., DixonC.E., ConleyY.P., BergaS., and WagnerA.K. (2013). Impact of aromatase genetic variation on hormone levels and global outcome after severe TBI. J. Neurotrauma, 30, 1415–1425.
24.
RoofR.L., and HallE.D. (2000). Estrogen-related gender difference in survival rate and cortical blood flow after impact-acceleration head injury in rats. J. Neurotrauma, 17, 1155–1169.
25.
RoofR.L., and HallE.D. (2000). Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J. Neurotrauma, 17, 367–388.
26.
WagnerA.K., McCulloughE.H., NiyonkuruC., OzawaH., LoucksT.L., DobosJ.A., BrettC.A., SantarsieriM., DixonC.E., BergaS.L., and FabioA. (2011). Acute serum hormone levels: characterization and prognosis after severe traumatic brain injury. J. Neurotrauma, 28, 871–888.
27.
YangS.H., PerezE., CutrightJ., LiuR., HeZ., DayA.L., and SimpkinsJ.W. (2002). Testosterone increases neurotoxicity of glutamate in vitro and ischemia-reperfusion injury in an animal model. J. Appl. Physiol., 92, 195–201.
28.
YangS.H., LiuR., WenY., PerezE., CutrightJ., Brun-ZinkernagelA.M., SinghM., DayA.L., and SimpkinsJ.W. (2005). Neuroendocrine mechanism for tolerance to cerebral ischemia-reperfusion injury in male rats. J. Neurobiol., 62, 341–351.
29.
CragoE.A., SherwoodP.R., BenderC., BalzerJ., RenD., and PoloyacS.M.. (2015). Plasma estrogen levels are associated with severity of injury and outcomes after aneurysmal subarachnoid hemorrhage. Biol. Res. Nurs., 17, 558–566.
30.
SternbachG.L. (2000). The Glasgow coma scale. J. Emerg. Med., 19, 67–71.
31.
KesingerM.R., JuengstS.B., BertischH., NiemeierJ.P., KrellmanJ.W., PughM.J., KumarR.G., SperryJ.L., ArenthP.M., FannJ.R., and WagnerA.K. (2016). Acute trauma factor associations with suicidality across the first 5 years after traumatic brain injury. Arch. Phys. Med. Rehabil., 97, 1301–1308.
32.
Social Security Death IndexSSDI Search at Ancestry.com. Available at: http://search.ancestry.com/search/db.aspx?dbid=3693. Last accessed august12, 2018.
33.
FakhryS.M., TraskA.L., WallerM.A., WattsD.D., and IRTC Neurotrauma TaskForce. (2004). Management of brain-injured patients by an evidence-based medicine protocol improves outcomes and decreases hospital charges. J. Trauma, 56, 492–499.
34.
HawkinsM.L., LewisF.D., and MedeirosR.S. (2005). Impact of length of stay on functional outcomes of TBI patients. Am. Surg., 71, 920–929.
35.
MurrayG.D., ButcherI., McHughG.S., LuJ., MushkudianiN.A., MaasA.I., MarmarouA., and SteyerbergE.W. (2007). Multivariable prognostic analysis in traumatic brain injury: results from the IMPACT study. J. Neurotrauma, 24, 329–337.
36.
FengJ.Y., LiuK.T., AbrahamE., ChenC.Y., TsaiP.-Y., ChenY.C., LeeY.C., and YangK.Y. (2014). Serum estradiol levels predict survival and acute kidney injury in patients with septic shock—a prospective study. PloS One, 9, e97967.
37.
ChristeffN., CarliA., BenassayagC., BleichnerG., VaxelaireJ.F., and NunezE.A. (1992). Relationship between changes in serum estrone levels and outcome in human males with septic shock. Circ. Shock, 36, 249–255.
38.
KauffmannR.M., NorrisP.R., JenkinsJ.M., DupontW.D., TorresR.E., BlumeJ.D., DossettL.A., HranjecT., SawyerR.G., and MayA.K. (2011). Trends in estradiol during critical illness are associated with mortality independent of admission estradiol. J. Am. Coll. Surg., 212, 703–712.
39.
ZolinS.J., VodovotzY., ForsytheR.M., RosengartM.R., NamasR., BrownJ.B., PeitzmanA.P., BilliarT.R., and SperryJ.L. (2015). The early evolving sex hormone environment is associated with significant outcome and inflammatory response differences after injury. J. Trauma Acute Care Surg., 78, 451–457.
40.
ChristeffN., BenassayagC., Carli-VielleC., CarliA., and NunezE.A. (1988). Elevated oestrogen and reduced testosterone levels in the serum of male septic shock patients. J. Steroid Biochem., 29, 435–440.
41.
FourrierF., JallotA., LeclercL., JourdainM., RacadotA., ChagnonJ.L., RimeA., and ChopinC. (1994). Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock. Circ. Shock, 43, 171–178.
42.
SprattD.I., LongcopeC., CoxP.M., BigosS.T., and Wilbur-WellingC. (1993). Differential changes in serum concentrations of androgens and estrogens (in relation with cortisol) in postmenopausal women with acute illness. J. Clin. Endocrinol. Metab., 76, 1542–1547.
43.
SprattD.I., MortonJ.R., KramerR.S., MayoS.W., LongcopeC., and VaryC.P. (2006). Increases in serum estrogen levels during major illness are caused by increased peripheral aromatization. Am. J. Physiol. Endocrinol. Metab., 291, E631–E638.
44.
ZhaoY., NicholsJ.E., BulunS.E., MendelsonC.R., and SimpsonE.R. (1995). Aromatase P450 gene expression in human adipose tissue. Role of a Jak/STAT pathway in regulation of the adipose-specific promoter. J. Biol. Chem., 270, 16449–16457.
45.
ZhaoY., MendelsonC.R., and SimpsonE.R. (1995). Characterization of the sequences of the human CYP19 (aromatase) gene that mediate regulation by glucocorticoids in adipose stromal cells and fetal hepatocytes. Mol. Endocrinol., 9, 340–349.
46.
ZhaoY., NicholsJ.E., ValdezR., MendelsonC.R., and SimpsonE.R. (1996). Tumor necrosis factor-alpha stimulates aromatase gene expression in human adipose stromal cells through use of an activating protein-1 binding site upstream of promoter 1.4. Mol. Endocrinol., 10, 1350–1357.
47.
SaltP.J., and IversonL.L. (1972). Inhibition of the extraneuronal uptake of catecholamine in the isolated rat heart by cholesterol. Nat. New Biol., 238, 91–92.
48.
SteffanR.J., MatelanE., AshwellM.A., MooreW.J., SolvibileW.R., TrybulskiE., ChadwickC.C., ChippariS., KenneyT., WinnekerR.C., EckertA., Borges-MarcucciL., AdelmanS.J., XuZ., MosyakL., and HarnishD.C. (2006). Control of chronic inflammation with pathway selective estrogen receptor ligands. Curr. Top. Med. Chem., 6, 103–111.
49.
HarnishD.C. (2006). Estrogen receptor ligands in the control of pathogenic inflammation. Curr. Opin. Investig. Drugs, 7, 997–1001.
50.
CristofaroP.A., OpalS.M., PalardyJ.E., ParejoN.A., JhungJ., KeithJ.C., and HarrisH.A. (2006). WAY-202196, a selective estrogen receptor-beta agonist, protects against death in experimental septic shock. Crit. Care Med., 34, 2188–2193.
51.
Cardozo JúniorL.C., and SilvaR.R.da. (2014). Sepsis in intensive care unit patients with traumatic brain injury: factors associated with higher mortality. Rev. Bras. Ter. Intensiva, 26, 148–154.
52.
Tahsili-FahadanP. and GeocadinR.G. (2017). Heart-brain axis: effects of neurologic injury on cardiovascular function. Circ. Res., 120, 559–572.
53.
van der JagtM. and MirandaD.R. (2012). Beta-blockers in intensive care medicine: potential benefit in acute brain injury and acute respiratory distress syndrome. Recent Pat. Cardiovasc. Drug Discov., 7, 141–151.
54.
SaatmanK.E., DuhaimeA.C., BullockR., MaasA.I.., ValadkaA., ManleyG.T., and Workshop Scientific Team and Advisory PanelMembers. (2008). Classification of traumatic brain injury for targeted therapies. J. Neurotrauma, 25, 719–738.
55.
McNettM. (2007). A review of the predictive ability of Glasgow Coma Scale scores in head-injured patients. J. Neurosci. Nurs., 39, 68–75.
56.
RoofR.L., DuvdevaniR., and SteinD.G. (1992). Progesterone treatment attenuates brain edema following contusion injury in male and female rats. Restor. Neurol. Neurosci., 4, 425–427.
57.
O'ConnorC.A., CernakI., and VinkR. (2005). Both estrogen and progesterone attenuate edema formation following diffuse traumatic brain injury in rats. Brain Res. 1062, 171–174.
58.
FeeserV.R. and LoriaR.M. (2011). Modulation of traumatic brain injury using progesterone and the role of glial cells on its neuroprotective actions. J. Neuroimmunol., 237, 4–12.
59.
GrossmanK.J., GossC.W., and SteinD.G. (2004). Effects of progesterone on the inflammatory response to brain injury in the rat. Brain Res. 1008, 29–39.
60.
IshratT., SayeedI., AtifF., HuaF., and SteinD.G. (2010). Progesterone and allopregnanolone attenuate blood-brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases. Exp. Neurol., 226, 183–190.
61.
Garcia-SeguraL.M., AzcoitiaI., and DonCarlosL.L. (2001). Neuroprotection by estradiol. Prog. Neurobiol., 63, 29–60.
62.
HersonP., KoernerI., and HurnP. (2009). Sex, sex steroids, and brain injury. Semin. Reprod. Med., 27, 229–239.
63.
SoustielJ.F., PalzurE., NevoO., ThalerI., and VlodavskyE. (2005). Neuroprotective anti-apoptosis effect of estrogens in traumatic brain injury. J. Neurotrauma, 22, 345–352.
64.
WrightD.W., YeattsS.D., SilbergleitR., PaleschY.Y., HertzbergV.S., FrankelM., GoldsteinF.C., CaveneyA.F., Howlett-SmithH., BengelinkE.M., ManleyG.T., MerckL.H., JanisL.S., BarsanW.G., and NETTInvestigators. (2014). Very early administration of progesterone for acute traumatic brain injury. N. Engl. J. Med., 371, 2457–2466.
65.
SkolnickB.E., MaasA.I., NarayanR.K., van der HoopR.G., MacAllisterT., WardJ.D., NelsonN.R., and StocchettiN.; SYNAPSETrial. (2014). A clinical trial of progesterone for severe traumatic brain injury. N. Engl. J. Med., 371, 2467–2476.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
