Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know

In the paper

“We found that overall, human studies report worse outcomes in women than men, whereas animal studies report better outcomes in females than males.”

In the paper

“For example, 76% of studies of > 10,000 patients used either S or CI as outcomes, whereas smaller studies relied on SB measures (66%, Table 2).”

In the paper

“In contrast, among studies of moderate-severe TBI, 34% found that women fared worse than men and a greater proportion (46%) showed that women fared better (Fig. 2, lower right).”

In the paper

“In studies of moderate-severe injury 52% used CI and/or S as outcomes, whereas only 30% included SB measures (Table 2).”

In the paper

“A majority of the smaller studies (52%) reported worse outcomes in women compared with men, with fewer (23%) reporting better outcomes in women (Fig. 3, left).”

In the paper

“Across all human studies, the largest fraction (47%) reported worse outcomes in women than men. 26% found better outcomes, in women, 18% found no sex difference, and only about 9% reported mixed results with women performing better on certain outcome measures and men on others (Fig, 2, upper panel).”

In the paper

“among large studies only 13% reported women faring worse. Moreover, most large studies reported that women did better than men (67%; Fig. 3, right).”

In the paper

“Non-stratified studies that did not segregate patients by injury severity were split between those that showed women faring better (33%) and those that showed women faring worse than men (40%), with 19% reporting no sex differences in TBI outcomes or pathology (Fig. 2, lower left).”

In the paper

“For example, a majority of studies of mild-moderate TBI found that women fared worse than men (60%), whereas only 9% of these reported better outcomes in women (Fig. 2, lower middle).”

In the paper

“Specifically, among studies of mild TBI, only 17% showed better outcomes in females than males, whereas in moderate-severe TBI a larger proportion (55%) showed better outcomes in females.”

In the paper

“Further, only 15% of studies specifically reported extracranial injury status, with similar numbers including versus excluding these patients.”

In the paper

“Although functional outcomes were reported in 149 of the 156 human studies, physiological/neuropathological measures were only reported in 24.”

In the paper

“Moreover, studies of severe TBI were more likely to use CI and S as outcome measures and to show better outcomes in women.”

In the paper

“Among all animal studies, 44% reported that females fared better than males, 14% reported that females fared worse, with the remaining studies showing no sex differences (28%) or mixed results (14%; Fig. 4, top).”

In the paper

“In contrast, mild TBI is associated with worse outcomes in women in clinical studies but mixed results in animal studies (Figs. 2 and 4).”

In the paper

“Most of the CCI studies (55%) reported better outcomes in females than males, with none showing males doing better (Fig. 5).”

In the paper

“As Figure 6 summarizes, among all human studies, women tend to do worse following TBI, whereas in animal studies, females tend to do better.”

In the paper

“In studies using CHI, 31% found females doing better and 23% showed females doing worse.”

In the paper

“Figures 2 and 4 indicate that 9% of human studies and 28% of animal studies yielded mixed results per our definition.”

In the paper

“Restricting analysis to studies reporting more than one outcome indicates that 19% of human and 37% of animal studies reported mixed results.”

In the paper

“Historically, preclinical studies in neurotrauma have been performed exclusively in males”

In the paper

“An array of outcome measures has been used to study sex differences in TBI in both humans and animals.”

In the paper

“Few studies have investigated potential effects of androgens or chromosomal contributions to sex differences in TBI outcomes.”

In the paper

“Most studies using the CCI model indicate that females do better and none show males with better outcomes.”

In the paper

“Fewer women than men are enrolled in clinical trials of TBI, in part because the incidence of TBI in men is far greater than in women.”

What the sources say

• Not checked yetcites [19] 19. Stein, D.G. (2015). Embracing failure: what the Phase III progesterone studies can teach about TBI clinical trials. Brain Inj. 29, 12591272.
• Not checked yetcites [21] 21. McCarthy, M.M., Pickett, L.A., VanRyzin, J.W., and Kight, K.E. (2015). Surprising origins of sex differences in the brain. Horm. Behav. 76, 3-10.
• Not checked yetcites [22] 22. Soldin, O.P., and Mattison, D.R. (2009). Sex differences in pharmacokinetics and pharmacodynamics. Clin. Pharmacokinet 48, 143-157.

In the paper

“Epidemiological data suggest that men are approximately 40% more likely to suffer a TBI compared with women in the general adult population, although the sex difference disappears above 75 years of age.”

What the sources say

• Not checked yetcites [1] 1. Faul, M., and Coronado, V. (2015). Epidemiology of traumatic brain injury. Handb. Clin. Neurol. 127, 3-13.
• Not checked yetcites [2] 2. Coronado, V.G., McGuire, L.C., Sarmiento, K., Bell, J., Lionbarger, M.R., Jones, C.D., Geller, A.I., Khoury, N., and Xu, L. (2012). Trends in traumatic brain injury in the U.S. and the public health response: 1995-2009. J. Safety Res. 43, 299-307.

In the paper

“First, are there differences in how men and women acquire their injuries? The answer appears to be yes, with women more likely to receive injuries from assault or violence in interpersonal relationships and men more likely to receive work-related injuries from falls and motor vehicle collisions.”

What the sources say

• Not checked yetcites [6] 6. Chang, V.C., Ruseckaite, R., Collie, A., and Colantonio, A. (2014). Examining the epidemiology of work-related traumatic brain injury through a sex/gender lens: analysis of workers' compensation claims in Victoria, Australia. Occup. Environ. Med. 71, 695-703.
• Not checked yetcites [7] 7. Colantonio, A. (2016). Sex, gender, and traumatic brain injury: A commentary. Arch. Physical Med. Rehabil. 97, S1-S4.
• Not checked yetcites [8] 8. Iverson, K.M., Hendricks, A.M., Kimerling, R., Krengel, M., Meterko, M., Stolzmann, K.L., Baker, E., Pogoda, T.K., Vasterling, J.J., and Lew, H.L. (2011). Psychiatric diagnoses and neurobehavioral symptom severity among OEF/OIF VA patients with deploymentrelated traumatic brain injury: a gender comparison. Women Health Iss. 21, S210-S217.

In the paper

“Second, are there differences in how the brains of men and women respond to an injury at the cellular and molecular level? Again, the answer appears to be yes, with genetics and sex hormones likely to influence inflammation, edema, oxidative stress, excitotoxicity, and mitochondrial function.”

What the sources say

• Not checked yetcites [9] 9. Demarest, T.G., and McCarthy, M.M. (2015). Sex differences in mitochondrial (dys)function: implications for neuroprotection. J. Bioenerg. Biomembr. 47, 173-188.
• Not checked yetcites [10] 10. Gunther, M., Plantman, S., Davidsson, J., Angeria, M., Mathiesen, T., and Risling, M. (2015). COX-2 regulation and TUNEL-positive cell death differ between genders in the secondary inflammatory response following experimental penetrating focal brain injury in rats. Acta Neurochir. (Wien) 157, 649-659.
• Not checked yetcites [11] 11. Roof, R.L., Duvdevani, R., and Stein, D.G. (1993). Gender influences outcome of brain injury: progesterone plays a protective role. Brain Res. 607, 333-336.
• Not checked yetcites [12] 12. Villapol, S., Loane, D.J., and Burns, M.P. (2017). Sexual dimorphism in the inflammatory response to traumatic brain injury. Glia 65, 1423-1438.
• Not checked yetcites [13] 13. Farin, A., Deutsch, R., Biegon, A., and Marshall, L.F. (2003). Sexrelated differences in patients with severe head injury: greater susceptibility to brain swelling in female patients 50 years of age and younger. J. Neurosurg. 98, 32-36.
• Not checked yetcites [14] 14. Wagner, A.K., Bayir, H., Ren, D., Puccio, A., Zafonte, R.D., and Kochanek, P.M. (2004). Relationships between cerebrospinal fluid markers of excitotoxicity, ischemia, and oxidative damage after severe TBI: the impact of gender, age, and hypothermia. J. Neurotrauma 21, 125-136.
• Not checked yetcites [15] 15. Wagner, A.K., Fabio, A., Puccio, A.M., Hirschberg, R., Li, W., Zafonte, R.D., and Marion, D.W. (2005). Gender associations with cerebrospinal fluid glutamate and lactate/pyruvate levels after severe traumatic brain injury. Crit. Care Med. 33, 407-413.

In the paper

“Although women have a lower prevalence of deployment-related TBI than men, as a growing number of women choose to serve in active military duty, their relative risk of sustaining combat-related injuries is likely to increase compared with their civilian counterparts.”

What the sources say

• Not checked yetcites [4] 4. Amoroso, T., and Iverson, K.M. (2017). Acknowledging the risk for traumatic brain injury in women veterans. J. Nerv. Ment. Dis. 205, 318-323.
• Not checked yetcites [5] 5. Amara, J.H., Stolzmann, K.L., Iverson, K.M., and Pogoda, T.K. (2018). Predictors of employment status in male and female Post-9/ 11 veterans evaluated for traumatic brain injury. J Head Trauma Rehabil. 34, 11-20.

In the paper

“Each and all of these factors might influence outcome in studies of sex differences in TBI.”

In the paper

“Decreased cadence on a dual gait-cognition task in adolescent girls indicating impaired executive function up to 2 weeks post-TBI.”

In the paper

“No differences GOS or mortality; CI, SB, S”

In the paper

“No difference in symptom severity; CI”

In the paper

“Lower excitotoxic oxidative damage in women”

In the paper

“More post-concussion symptoms and worse GOS-E in women at 3 months post-injury; SB; CI”

In the paper

“More nausea, light sensitivity, change in taste/smell and appetite, and poor sleep-related symptoms in women vs. age-matched men;”

In the paper

“Higher rates of injury and longer recovery times in women soccer basketball players; CI”

In the paper

“No differences in cognitive tests between men and women; SB”

In the paper

“Better executive function in women; SB”

In the paper

“Shorter duration of post-traumatic amnesia in women.”

In the paper

“More verbal memory deficits in women but no differences on tasks, neurobehavioral symptoms, or chronic stress; SB”

In the paper

“Greater symptom severity and longer time to return to baseline performance in women athletes; CI, SB”

In the paper

“Better quality of life 8-24 years after TBI in women; CI”

In the paper

“This may be because patients surviving severe TBI are less likely to complete detailed cognitive testing, whereas a study of survival in patients with mild TBI might suffer from ceiling effects because few patients will die.”

In the paper

“difference in sleep disturbance after multiple concussions; SB”

In the paper

“More post-concussive symptoms in women at 3 months post-TBI, mainly child-bearing age; SB”

In the paper

“Faster processing speed and reaction time in women athletes.”

In the paper

“Increased sleep disturbance after single concussion in women, especially those above age 15.”

In the paper

“When comparing these trends with sex difference findings across study size (Fig. 3), it seems that SB outcome measures used in smaller studies correspond to worse outcomes in women. In contrast, larger studies that use CI and S were more likely to report women faring better than men.”

In the paper

“Higher mortality in the ICU and 6 months post-TBI in women.”

In the paper

“No differences in GOS 5 days post-TBI; CI”

In the paper

“Depression exacerbated over time in women, but resolved over time men; SB”

In the paper

“Such a system of classification is unbiased because it avoids judgments on the relative importance of each outcome/symptom.”

In the paper

“Lower risk of mortality in women compared with men; S”

• Also stated in: § Table 1. Human Studies of TBI Comparing Outcomes by Sex · plain

  “Lower mortality in women; S”

• Also stated in: § Table 1. Human Studies of TBI Comparing Outcomes by Sex · plain

  “Lower risk of post-injury mortality in women; S”

In the paper

“More post-concussion symptoms in women, but no differences rate, loss of consciousness, amnesia, or confusion; SB”

In the paper

“More women experienced post-concussion symptoms and disability, but differences in life satisfaction 3 years post-injury; SB; CI”

In the paper

“Lower mortality in women after blunt force injury; S”

In the paper

“Sustained hypoactivation in fMRI activity during memory tasks”

In the paper

“Higher risk of mortality in women in China; S”

In the paper

“Better scores on verbal memory in girls at 1 year post-injury;”

In the paper

“More depressive symptoms in women; SB”

In the paper

“No differences eye coordination or balance; SB”

In the paper

“Less withdrawal and better social skills in girls 1 year post-TBI;”

In the paper

“More vestibulo-oculomotor impairment and longer time to symptom resolution in women.”

In the paper

“More post-concussive symptoms in adult women (ages 18-59) but not minor girls (ages 4-17), at 3 months post-TBI compared with men: SB”

In the paper

“More post-concussive symptoms and worse performance on tasks in women athletes up to 2 weeks post-TBI; SB”

In the paper

“Better visual memory in women.”

In the paper

“More women with minor TBI were depressed and had incomplete return work 6-12 months post-TBI than men with similar injury severity; SB; CI”

In the paper

“No differences incidence of neuropathic pain following TBI; SB”

In the paper

“Better work capacity outcomes in women; CI”

In the paper

“More post-traumatic headaches and longer recovery time 1-3 weeks post- TBI in women; SB”

In the paper

“Prolonged post-concussive symptoms 3 months post-TBI in women;”

In the paper

“More post-concussive symptoms due to increased anxiety sensitivity”

In the paper

“Subsequently, the paucity of women in clinical trials means that promising treatments are not being tested against the real biological substrate and may hamper translational success.”

In the paper

“level of oxidative damage correlated with GOS in women but not men”

In the paper

“Better survival rates in post-menopausal women.”

In the paper

“This is likely because smaller studies can collect data prospectively from individual patients, whereas very large studies tend to extract data retrospectively from existing databases including medical records.”

In the paper

“Higher severity and more concussion symptoms in women.”

In the paper

“Worse neurocognitive performance and more post-concussion symptoms girls; SB”

In the paper

“Because brain anatomy, cellular pathways, and drug pharmacokinetics can be affected by biological sex, 21,22”

What the sources say

• Not checked yetcites [21] 21. McCarthy, M.M., Pickett, L.A., VanRyzin, J.W., and Kight, K.E. (2015). Surprising origins of sex differences in the brain. Horm. Behav. 76, 3-10.
• Not checked yetcites [22] 22. Soldin, O.P., and Mattison, D.R. (2009). Sex differences in pharmacokinetics and pharmacodynamics. Clin. Pharmacokinet 48, 143-157.

In the paper

“The workshop acknowledged that findings to date have been mixed, and concluded that numerous knowledge gaps still exist regarding the effects of sex in TBI.”

In the paper

“More post-concussion symptoms and greater in vestibular reflexes in girls up to 3 weeks post-TBI.”

In the paper

“Shorter length of hospital stay and better outcomes on 3-month women; CI”

In the paper

“More impaired empathy in women post-TBI; SB”

In the paper

“More severe post-concussion symptoms and anxiety in women; SB”

In the paper

“Shorter comprehension times in men;”

In the paper

“Better emotion recognition in women.”

In the paper

“No difference in symptom recovery or cognitive recovery; SB”

In the paper

“More headaches and dizziness in women;”

In the paper

“No differences in neurocognitive abilities; SB”

In the paper

“No difference in sleep architecture; SB”

In the paper

“better memory and immediate recall women; SB”

In the paper

“Lower cerebral perfusion pressure, higher intracranial pressure, and greater frequency of cerebral edema may contribute to higher mortality and unfavorable GOS 1 month postTBI in women. 13,24,25”

What the sources say

• Not checked yetcites [13] 13. Farin, A., Deutsch, R., Biegon, A., and Marshall, L.F. (2003). Sexrelated differences in patients with severe head injury: greater susceptibility to brain swelling in female patients 50 years of age and younger. J. Neurosurg. 98, 32-36.
• Not checked yetcites [24] 24. Balestreri, M., Steiner, L.A., and Czosnyka, M. (2003). Sex-related differences and traumatic brain injury. J. Neurosurg. 99, 616; author reply 616-617.
• Not checked yetcites [25] 25. Czosnyka, M., Radolovich, D., Balestreri, M., Lavinio, A., Hutchinson, P., Timofeev, I., Smielewski, P., and Pickard, J.D. (2008). Gender-related differences in intracranial hypertension and outcome after traumatic brain injury. Acta Neurochir. Suppl. 102, 25-28.

In the paper

“No difference in 6-month GOS; S”

In the paper

“Higher levels of dopamine metabolites in CSF of women”

In the paper

“Systolic blood pressure was in pubescent and pre- pubescent girls than in boys;”

In the paper

“No differences in frequency or severity of chronic pain; SB”

In the paper

“No incidence hyponatremia post-TBI”

In the paper

“Fewer cerebral micro-bleeds post- concussion in women hockey players”

In the paper

“Additionally, race may interact with sex to influence TBI outcomes, with a study of nearly 3000 patients with mild to severe TBI finding higher incidence of brain edema in women sampled in Hong Kong but not those in Australia. 30”

What the sources say

• Not checked yetcites [30] 30. Yeung, J.H., Mikocka-Walus, A.A., Cameron, P.A., Poon, W.S., Ho, H.F., Chang, A., Graham, C.A., and Rainer, T.H. (2011). Protection from traumatic brain injury in hormonally active women vs. men of a similar age: a retrospective international study. Arch. Surg. 146, 436-442.

In the paper

“No difference in insomnia prevalence or severity 3 months post-TBI;”

In the paper

“No difference in serum of oxidative stress trauma”

In the paper

“No difference in mortality or GOS at discharge.”

In the paper

“No difference in unemployment rate between men and women veterans;”

In the paper

“No sex difference in diffuse axonal injury, brain edema, hypoxia, ICP, contusional bleeding;”

In the paper

“No difference in duration of symptoms, or SB”

In the paper

“sex differences in lesions on CT scans”

In the paper

“No differences in mortality, injury severity, or incidence of acute complications post-TBI; SB, S”

In the paper

“These differences could be attributed to race-specific single nucleotide polymorphisms in genes affecting inflammation and predisposition to genetic diseases. 31,32”

What the sources say

• Not checked yetcites [31] 31. Huang, T., Shu, Y., and Cai, Y.D. (2015). Genetic differences among ethnic groups. BMC Genomics 16, 1093.
• Not checked yetcites [32] 32. Van Dyke, A.L., Cote, M.L., Wenzlaff, A.S., Land, S., and Schwartz, A.G. (2009). Cytokine SNPs: comparison of allele frequencies by race and implications for future studies. Cytokine 46, 236-244.

In the paper

“No differences in number of post-concussive symptoms, neurocognitive scores or depression up to 2 weeks post-injury; SB”

In the paper

“No differences in concussion symptom reporting or cognition in hockey players 6 months post-injury; SB”

In the paper

“Lower rates fogginess, memory impairment, and concentration problems”

In the paper

“Lower mortalityin girls; S”

In the paper

“No differences in mild depression 1-year post-injury; SB”

In the paper

“Shorter hospital stay and better attention, working memory, and language skills 1 year post-TBI in women;”

In the paper

“No motor outcomes or perceived life satisfaction; SB”

In the paper

“Better executive function in women due to greater self-awareness related deficits; SB”

In the paper

“No difference in visuo-spatial abilities; SB”

In the paper

“No difference in postural control and balance post-TBI; CI”

In the paper

“No difference in cognition or symptoms in soccer players 6 months post- TBI; SB”

In the paper

“Higher fractional anisotropy (indicative of white matter integrity) in women”

In the paper

“No difference in symptom reporting in women.”

In the paper

“No difference in neuropsychological performance 2 post-TBI;”

In the paper

“No difference in neurocognitive ability or number of symptoms in high school soccer players; SB”

In the paper

“Less physical aggression in women veterans”

In the paper

“but no differences depression; SB”

In the paper

“Better visual memory in men athletes;”

In the paper

“No differences in injury severity, GOS, or length of stay in rehabilitation;”

In the paper

“Better post-concussion performance in women; SB”

In the paper

“No difference in balance and postural stability; CI”

In the paper

“No differences in length of hospital stay, GOS-E, or functional independence 3.5 years post-TBI; CI, S”

In the paper

“However, severe CCI did not show significant difference in time-course of neurodegeneration or in overall tissue damage between males and females. 43”

What the sources say

• Not checked yetcites [43] 43. Hall, E.D., Gibson, T.R., and Pavel, K.M. (2005). Lack of a gender difference in post-traumatic neurodegeneration in the mouse controlled cortical impact injury model. J. Neurotrauma 22, 669-679.

In the paper

“Animal studies offer the ability to control many experimental variables, to study cellular and molecular mechanisms, and to directly test the link between mechanisms and functional outcomes.”

In the paper

“For instance, cell death following brain injury is triggered by caspase activation in females but by caspase-independent mechanisms in males. 9”

What the sources say

• Not checked yetcites [9] 9. Demarest, T.G., and McCarthy, M.M. (2015). Sex differences in mitochondrial (dys)function: implications for neuroprotection. J. Bioenerg. Biomembr. 47, 173-188.

In the paper

“Normally cycling females had significantly better survival rates, blood-brain barrier integrity, improved cortical blood flow, fewer sensorimotor deficits, less brain edema, and smaller contusion volumes than age-matched males after TBI. 11,60-62”

What the sources say

• Not checked yetcites [11] 11. Roof, R.L., Duvdevani, R., and Stein, D.G. (1993). Gender influences outcome of brain injury: progesterone plays a protective role. Brain Res. 607, 333-336.
• Not checked yetcites [60] 60. Roof, R.L., and Hall, E.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.
• Not checked yetcites [61] 61. Bramlett, H.M., and Dietrich, W.D. (2001). Neuropathological protection after traumatic brain injury in intact female rats versus males or ovariectomized females. J. Neurotrauma 18, 891-900.
• Not checked yetcites [62] 62. Clevenger, A.C., Kim, H., Salcedo, E., Yonchek, J.C., Rodgers, K.M., Orfila, J.E., Dietz, R.M., Quillinan, N., Traystman, R.J., and Herson, P.S. (2018). Endogenous sex steroids dampen neuroinflammation and improve outcome of traumatic brain injury in mice. J. Mol. Neurosci. 64, 410-420.

In the paper

“Similarly, female rats in the proestrous phase of their cycles had less brain edema and lower intracranial pressure after TBI compared with non-proestrous females presumably due to elevated serum levels of estrogen and progesterone. 64”

What the sources say

• Not checked yetcites [64] 64. Maghool, F., Khaksari, M., and Siahposht Khachki, A. (2013). Differences in brain edema and intracranial pressure following traumatic brain injury across the estrous cycle: involvement of female sex steroid hormones. Brain Res. 1497, 61-72.

In the paper

“Considering the current body of research on sex differences in TBI, the overall picture is not a straightforward one that points to better outcomes in one sex versus the other. Rather, the findings we have reviewed from human and animal studies are complicated and often contradictory.”

In the paper

“As noted above, human studies more commonly report functional outcomes after TBI, whereas animal studies more frequently report measures related to cellular or molecular mechanism.”

In the paper

“Such symptoms are usually self-reported and may be influenced by societal gender stereotypes resulting in men reporting symptoms differently from women. 53,54”

What the sources say

• Not checked yetcites [53] 53. Maclean, A., Sweeting, H., and Hunt, K. (2010). 'Rules' for boys, 'guidelines' for girls: gender differences in symptom reporting during childhood and adolescence. Soc. Sci. Med. 70, 597-604.
• Not checked yetcites [54] 54. Wallace, J., Covassin, T., and Beidler, E. (2017). Sex differences in high school athletes' knowledge of sport-related concussion symptoms and reporting behaviors. J. Athl. Train. 52, 682-688.

In the paper

“Females performed better than males on sensorimotor tasks but not on cognitive tasks following moderate to severe CCI. 37-40”

What the sources say

• Not checked yetcites [37] 37. Free, K.E., Greene, A.M., Bondi, C.O., Lajud, N., de la Tremblaye, P.B., and Kline, A.E. (2017). Comparable impediment of cognitive function in female and male rats subsequent to daily administration of haloperidol after traumatic brain injury. Exp. Neurol. 296, 62-68.
• Not checked yetcites [38] 38. Wagner, A.K., Willard, L.A., Kline, A.E., Wenger, M.K., Bolinger, B.D., Ren, D., Zafonte, R.D., and Dixon, C.E. (2004). Evaluation of estrous cycle stage and gender on behavioral outcome after experimental traumatic brain injury. Brain Res. 998, 113-121.
• Not checked yetcites [39] 39. Xu, X., Cao, S., Chao, H., Liu, Y., and Ji, J. (2016). Sex-related differences in striatal dopaminergic system after traumatic brain injury. Brain Res. Bull. 124, 214-221.
• Not checked yetcites [40] 40. Xiong, Y., Mahmood, A., Lu, D., Qu, C., Goussev, A., Schallert, T., and Chopp, M. (2007). Role of gender in outcome after traumatic brain injury and therapeutic effect of erythropoietin in mice. Brain Res. 1185, 301-312.

In the paper

“In adolescent male mice with TBI, progesterone improved motor performance but exacerbated deficits in female mice. 66”

What the sources say

• Not checked yetcites [66] 66. Mannix, R., Berglass, J., Berkner, J., Moleus, P., Qiu, J., Jantzie, L.L., Meehan, W.P., 3rd, Stanley, R.M., and Robinson, S. (2014). Sex differences in the effect of progesterone after controlled cortical impact in adolescent mice: a preliminary study. J. Neurosurg. 121, 1337-1341.

In the paper

“One study suggests that the better post-injury outcome in pseudopregnant females compared with both males and intact females might be due to their 50-100 times higher levels of progesterone and its metabolites at the time of injury. 63”

What the sources say

• Not checked yetcites [63] 63. Meffre, D., Pianos, A., Liere, P., Eychenne, B., Cambourg, A., Schumacher, M., Stein, D.G., and Guennoun, R. (2007). Steroid profiling in brain and plasma of male and pseudopregnant female rats after traumatic brain injury: analysis by gas chromatography/mass spectrometry. Endocrinology 148, 2505-2517.

In the paper

“Regarding timecourse, females showed less edema than males at 5 h, 3 days, and 5 days after impact acceleration injury, but more edema at 24 h post-injury. 41”

What the sources say

• Not checked yetcites [41] 41. O'Connor, C.A., Cernak, I., and Vink, R. (2006). The temporal profile of edema formation differs between male and female rats following diffuse traumatic brain injury. Acta Neurochir. Suppl. 96, 121-124.

In the paper

“In mice, dysfunction of the hypothalamic-pituitaryadrenal (HPA) axis following blast TBI is caused by dysregulation of pre-autonomic neurons in females, but by disruption of limbic pathways in males. 58”

What the sources say

• Not checked yetcites [58] 58. Russell, A.L., Richardson, M.R., Bauman, B.M., Hernandez, I.M., Saperstein, S., Handa, R.J., and Wu, T.J. (2018). Differential responses of the HPA axis to mild blast traumatic brain injury in male and female mice. Endocrinology 159, 2363-2375.

In the paper

“Mixed results within an animal study may also result from pre-set group sizes that are powered to detect sex differences in some assessments but might be inadequate for others.”

In the paper

“In addition, female mice had better ambulation and displayed less anxiety post-TBI although sex differences in brain lesion volumes were not detected. 49,51”

What the sources say

• Not checked yetcites [49] 49. Tucker, L.B., Fu, A.H., and McCabe, J.T. (2016). Performance of male and female C57BL/6J mice on motor and cognitive tasks commonly used in pre-clinical traumatic brain injury research. J. Neurotrauma 33, 880-894.
• Not checked yetcites [51] 51. Tucker, L.B., Burke, J.F., Fu, A.H., and McCabe, J.T. (2017). Neuropsychiatric symptom modeling in male and female C57BL/6J mice after experimental traumatic brain injury. J. Neurotrauma 34, 890-905.

In the paper

“In pseudo-pregnant rats, post-TBI cerebral edema was even lower than in normally cycling females, suggesting that female sex hormones may exert a dose-dependent neuroprotective response. 11”

What the sources say

• Not checked yetcites [11] 11. Roof, R.L., Duvdevani, R., and Stein, D.G. (1993). Gender influences outcome of brain injury: progesterone plays a protective role. Brain Res. 607, 333-336.

In the paper

“Conversely, sex-dependent neuroprotective effects were extinguished in ovariectomized females with low levels of circulating estrogen and progesterone, but rescued by exogenous treatment with these hormones. 11,60,61”

What the sources say

• Not checked yetcites [11] 11. Roof, R.L., Duvdevani, R., and Stein, D.G. (1993). Gender influences outcome of brain injury: progesterone plays a protective role. Brain Res. 607, 333-336.
• Not checked yetcites [60] 60. Roof, R.L., and Hall, E.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.
• Not checked yetcites [61] 61. Bramlett, H.M., and Dietrich, W.D. (2001). Neuropathological protection after traumatic brain injury in intact female rats versus males or ovariectomized females. J. Neurotrauma 18, 891-900.

In the paper

“At the ultrastructural level, axons of cultured neurons isolated from females were consistently smaller and contained fewer microtubules than those from males.”

What the sources say

• Not checked yetcites [102] 102. Dolle, J.P., Jaye, A., Anderson, S.A., Ahmadzadeh, H., Shenoy, V.B., and Smith, D.H. (2018). Newfound sex differences in axonal structure underlie differential outcomes from in vitro traumatic axonal injury. Exp. Neurol. 300, 121-134.

In the paper

“In contrast, chronically treating mice with an androgenic-anabolic steroid cocktail containing testosterone prior to induction of repeated, mild TBI exacerbated TBI-mediated axonal injury and white matter microgliosis but not behavioral deficits. 85”

What the sources say

• Not checked yetcites [85] 85. Namjoshi, D.R., Cheng, W.H., Carr, M., Martens, K.M., Zareyan, S., Wilkinson, A., McInnes, K.A., Cripton, P.A., and Wellington, C.L. (2016). Chronic exposure to androgenic-anabolic steroids exacerbates axonal injury and microgliosis in the CHIMERA mouse model of repetitive concussion. PLoS One 11, e0146540.

In the paper

“Further, age interacted with sex leading to better verbal abilities in women than men in their twenties but slower processing speed in women than men in their forties. 110”

What the sources say

• Not checked yetcites [110] 110. Eramudugolla, R., Bielak, A.A., Bunce, D., Easteal, S., Cherbuin, N., and Anstey, K.J. (2014). Long-term cognitive correlates of traumatic brain injury across adulthood and interactions with APOE genotype, sex, and age cohorts. J. Int. Neuropsychol. Soc. 20, 444-454.

In the paper

“These studies, which show within a given population sample that males fare better on some outcome measures and females better on others, encourage us to think about sex effects in TBI beyond a single dimension.”

In the paper

“In addition, the selection of outcome measures clearly matters and can affect conclusions.”

In the paper

“However, because testosterone is converted to estradiol by aromatase, there is a possibility that the observed effects are at least partly conferred by its estrogenic metabolite.”

In the paper

“Although many studies have focused on the hormonal basis of sex differences in TBI, chromosomal differences remain underexplored.”

In the paper

“For example, although women veterans were less likely to be diagnosed with post-traumatic stress disorder following TBI, they were more likely to suffer from depression or anxiety. 8”

What the sources say

• Not checked yetcites [8] 8. Iverson, K.M., Hendricks, A.M., Kimerling, R., Krengel, M., Meterko, M., Stolzmann, K.L., Baker, E., Pogoda, T.K., Vasterling, J.J., and Lew, H.L. (2011). Psychiatric diagnoses and neurobehavioral symptom severity among OEF/OIF VA patients with deploymentrelated traumatic brain injury: a gender comparison. Women Health Iss. 21, S210-S217.

In the paper

“Post-TBI symptoms differed between sexes with women reporting more headaches, dizziness, and drowsiness and men reporting more amnesia and confusion. 100,109”

What the sources say

• Not checked yetcites [100] 100. Frommer, L.J., Gurka, K.K., Cross, K.M., Ingersoll, C.D., Comstock, R.D., and Saliba, S.A. (2011). Sex differences in concussion symptoms of high school athletes. J. Athl. Train. 46, 76-84.
• Not checked yetcites [109] 109. Colantonio, A., Harris, J.E., Ratcliff, G., Chase, S., and Ellis, K. (2010). Gender differences in self reported long term outcomes following moderate to severe traumatic brain injury. BMC Neurol. 10, 102.

In the paper

“Behavioral studies in the same rats also found increased depression-like behaviors in females and working memory deficits in males. 45”

What the sources say

• Not checked yetcites [45] 45. Wright, D.K., O'Brien, T.J., Shultz, S.R., and Mychasiuk, R. (2017). Sex matters: repetitive mild traumatic brain injury in adolescent rats. Ann. Clin. Transl. Neurol. 4, 640-654.

In the paper

“High-resolution MRI in these mice found that sex differences in the volumes of certain brain regions were influenced exclusively by gonadal hormones, whereas differences in others were exclusively under chromosomal control.”

What the sources say

• Not checked yetcites [92] 92. Corre, C., Friedel, M., Vousden, D.A., Metcalf, A., Spring, S., Qiu, L.R., Lerch, J.P., and Palmert, M.R. (2016). Separate effects of sex hormones and sex chromosomes on brain structure and function revealed by high-resolution magnetic resonance imaging and spatial navigation assessment of the Four Core Genotype mouse model. Brain Struct. Funct. 221, 997-1016.

In the paper

“For example, female mice had fewer deficits in social recognition, but increased sociosexual avoidance compared with males following CCI, 51 and also showed greater ambulation but more severely depleted striatal dopamine compared with males. 39”

What the sources say

• Not checked yetcites [51] 51. Tucker, L.B., Burke, J.F., Fu, A.H., and McCabe, J.T. (2017). Neuropsychiatric symptom modeling in male and female C57BL/6J mice after experimental traumatic brain injury. J. Neurotrauma 34, 890-905.
• Not checked yetcites [39] 39. Xu, X., Cao, S., Chao, H., Liu, Y., and Ji, J. (2016). Sex-related differences in striatal dopaminergic system after traumatic brain injury. Brain Res. Bull. 124, 214-221.

In the paper

“Testosterone promotes neurogenesis in uninjured male rats 82 and neuronal survival in male and female rats following axonal injury. 83,84”

What the sources say

• Not checked yetcites [82] 82. Spritzer, M.D., and Galea, L.A. (2007). Testosterone and dihydrotestosterone, but not estradiol, enhance survival of new hippocampal neurons in adult male rats. Dev. Neurobiol. 67, 13211333.
• Not checked yetcites [83] 83. Yu, W.H. (1989). Administration of testosterone attenuates neuronal loss following axotomy in the brain-stem motor nuclei of female rats. J. Neurosci. 9, 3908-3914.
• Not checked yetcites [84] 84. Tehranipour, M., and Moghimi, A. (2010). Neuroprotective effects of testosterone on regenerating spinal cord motoneurons in rats. J. Mot. Behav. 42, 151-155.

In the paper

“The effect of sex hormones on neurogenesis and spine density has also been studied, 103-105 and could modulate synaptic plasticity during recovery from TBI.”

What the sources say

• Not checked yetcites [103] 103. Galea, L.A., Spritzer, M.D., Barker, J.M., and Pawluski, J.L. (2006). Gonadal hormone modulation of hippocampal neurogenesis in the adult. Hippocampus 16, 225-232.
• Not checked yetcites [104] 104. Keil, K.P., Sethi, S., Wilson, M.D., Chen, H., and Lein, P.J. (2017). In vivo and in vitro sex differences in the dendritic morphology of developing murine hippocampal and cortical neurons. Sci. Rep. 7, 8486.
• Not checked yetcites [105] 105. Shors, T.J., Chua, C., and Falduto, J. (2001). Sex differences and opposite effects of stress on dendritic spine density in the male versus female hippocampus. J. Neurosci. 21, 6292-6297. source

In the paper

“Given the importance of the amygdala, hippocampus, and prefrontal cortex for stress responses and mood, 97-99 it is possible that anatomical differences in these regions may contribute to post-TBI symptoms, as women report greater anxiety and depression and men report more amnesia and confusion. 8,100,101”

What the sources say

• Not checked yetcites [97] 97. Bangasser, D.A., and Valentino, R.J. (2014). Sex differences in stress-related psychiatric disorders: neurobiological perspectives. Front. Neuroendocrinol. 35, 303-319. source
• Not checked yetcites [98] 98. Gobinath, A.R., Mahmoud, R., and Galea, L.A. (2014). Influence of sex and stress exposure across the lifespan on endophenotypes of depression: focus on behavior, glucocorticoids, and hippocampus. Front. Neurosci. 8, 420.
• Not checked yetcites [99] 99. McEwen, B.S. (2010). Stress, sex, and neural adaptation to a changing environment: mechanisms of neuronal remodeling. Ann. N Y Acad. Sci. 1204 Suppl., E38-E59.
• Not checked yetcites [8] 8. Iverson, K.M., Hendricks, A.M., Kimerling, R., Krengel, M., Meterko, M., Stolzmann, K.L., Baker, E., Pogoda, T.K., Vasterling, J.J., and Lew, H.L. (2011). Psychiatric diagnoses and neurobehavioral symptom severity among OEF/OIF VA patients with deploymentrelated traumatic brain injury: a gender comparison. Women Health Iss. 21, S210-S217.
• Not checked yetcites [100] 100. Frommer, L.J., Gurka, K.K., Cross, K.M., Ingersoll, C.D., Comstock, R.D., and Saliba, S.A. (2011). Sex differences in concussion symptoms of high school athletes. J. Athl. Train. 46, 76-84.

In the paper

“Accordingly, sex differences in cerebellar and pre-central gray matter volumes were associated with X-chromosome load, whereas sex differences in the amygdala, parahippocampus, and occipital cortex were linked to testosterone levels. 96”

What the sources say

• Not checked yetcites [96] 96. Lentini, E., Kasahara, M., Arver, S., and Savic, I. (2013). Sex differences in the human brain and the impact of sex chromosomes and sex hormones. Cereb. Cortex 23, 2322-2336.

In the paper

“neuroprotective effects of testosterone including inhibition of apoptosis, reduction in oxidative stress, improved mitochondrial respiration, and maintenance of mitochondrial membrane potential have also been reported.”

What the sources say

• Not checked yetcites [144] 144. Chisu, V., Manca, P., Lepore, G., Gadau, S., Zedda, M., and Farina, V. (2006). Testosterone induces neuroprotection from oxidative stress. Effects on catalase activity and 3-nitro-L-tyrosine incorporation into alpha-tubulin in a mouse neuroblastoma cell line. Arch. Ital. Biol. 144, 63-73.
• Not checked yetcites [145] 145. Fanaei, H., Karimian, S.M., Sadeghipour, H.R., Hassanzade, G., Kasaeian, A., Attari, F., Khayat, S., Ramezani, V., and Javadimehr, M. (2014). Testosterone enhances functional recovery after stroke through promotion of antioxidant defenses, BDNF levels and neurogenesis in male rats. Brain Res. 1558, 74-83.
• Not checked yetcites [146] 146. Toro-Urrego, N., Garcia-Segura, L.M., Echeverria, V., and Barreto, G.E. (2016). Testosterone protects mitochondrial function and regulates neuroglobin expression in astrocytic cells exposed to glucose deprivation. Front. Aging Neurosci. 8, 152.

In the paper

“during high-stress conditions males preferentially rely on carbohydrates and amino acids as a fuel source for energy production, whereas females use fats.”

What the sources say

• Not checked yetcites [116] 116. Manole, M.D., Tehranian-DePasquale, R., Du, L., Bayir, H., Kochanek, P.M., and Clark, R.S. (2011). Unmasking sex-based disparity in neuronal metabolism. Curr. Pharm. Des. 17, 3854-3860.
• Not checked yetcites [126] 126. Widdowson, E.M. (1976). The response of the sexes to nutritional stress. Proc. Nutr. Soc. 35, 175-180.
• Not checked yetcites [127] 127. Lamont, L.S. (2005). Gender differences in amino acid use during endurance exercise. Nutr. Rev. 63, 419-422.
• Not checked yetcites [128] 128. Du, L., Hickey, R.W., Bayir, H., Watkins, S.C., Tyurin, V.A., Guo, F., Kochanek, P.M., Jenkins, L.W., Ren, J., Gibson, G., Chu, C.T., Kagan, V.E., and Clark, R.S. (2009). Starving neurons show sex difference in autophagy. J. Biol. Chem. 284, 2383-2396.

In the paper

“Mitochondria are crucial to energy production, as well as calcium homeostasis, free radical production, neurotransmitter synthesis, and apoptosis in neurons and glia.”

What the sources say

• Not checked yetcites [115] 115. Mattson, M.P., Gleichmann, M., and Cheng, A. (2008). Mitochondria in neuroplasticity and neurological disorders. Neuron 60, 748-766. source

In the paper

“A useful framework for understanding sex differences in TBI may be a ''mosaic'' model in which distinct anatomical/functional domains may each respond differently to injury in males versus females.”

In the paper

“Cellular stressors such as nutrient deprivation may elicit a differential response in mitochondria from males and females resulting in decreased mitochondrial respiration, increased autophagy, and enhanced neuronal death in male rats.”

What the sources say

• Not checked yetcites [128] 128. Du, L., Hickey, R.W., Bayir, H., Watkins, S.C., Tyurin, V.A., Guo, F., Kochanek, P.M., Jenkins, L.W., Ren, J., Gibson, G., Chu, C.T., Kagan, V.E., and Clark, R.S. (2009). Starving neurons show sex difference in autophagy. J. Biol. Chem. 284, 2383-2396.

In the paper

“brain mitochondria of female rodents had lower oxidative stress than those from males associated with greater expression and activity of antioxidant enzymes.”

What the sources say

• Not checked yetcites [119] 119. Gaignard, P., Savouroux, S., Liere, P., Pianos, A., Therond, P., Schumacher, M., Slama, A., and Guennoun, R. (2015). Effect of sex differences on brain mitochondrial function and its suppression by ovariectomy and in aged mice. Endocrinology 156, 2893-2904.
• Not checked yetcites [124] 124. Borras, C., Sastre, J., Garcia-Sala, D., Lloret, A., Pallardo, F.V., and Vina, J. (2003). Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic. Biol. Med. 34, 546-552. source
• Not checked yetcites [125] 125. Pinto, R.E., and Bartley, W. (1969). The effect of age and sex on glutathione reductase and glutathione peroxidase activities and on aerobic glutathione oxidation in rat liver homogenates. Biochem. J112, 109-115.

In the paper

“Although studies relying on a single outcome measure might be useful for gross outcomes such as mortality and are easier to interpret, they do not fully represent the anatomical and physiological complexity of sex effects in TBI.”

In the paper

“fission facilitates transport of mitochondria to regions of high energy demand and removal of damaged mitochondria by autophagy.”

What the sources say

• Not checked yetcites [132] 132. Bereiter-Hahn, J., and Voth, M. (1994). Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc. Res. Tech. 27, 198-219.
• Not checked yetcites [133] 133. Chan, D.C. (2006). Mitochondrial fusion and fission in mammals. Annu. Rev. Cell Dev. Biol. 22, 79-99. source

In the paper

“Such a model can account for mixed results, and highlights the benefits of study design that includes multiple outcome measurements. 48,111”

What the sources say

• Not checked yetcites [48] 48. McCarthy, M.M., Arnold, A.P., Ball, G.F., Blaustein, J.D., and De Vries, G.J. (2012). Sex differences in the brain: the not so inconvenient truth. J. Neurosci. 32, 2241-2247. source
• Not checked yetcites [111] 111. Joel, D., and Fausto-Sterling, A. (2016). Beyond sex differences: new approaches for thinking about variation in brain structure and function. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 371, 20150451.

In the paper

“Progesterone treatment reversed TBI-mediated impairment in mitochondrial respiration and neuron loss in ovariectomized adult females”

What the sources say

• Not checked yetcites [65] 65. Robertson, C.L., and Saraswati, M. (2015). Progesterone protects mitochondrial function in a rat model of pediatric traumatic brain injury. J. Bioenerg. Biomembr. 47, 43-51.
• Not checked yetcites [143] 143. Robertson, C.L., Puskar, A., Hoffman, G.E., Murphy, A.Z., Saraswati, M., and Fiskum, G. (2006). Physiologic progesterone reduces mitochondrial dysfunction and hippocampal cell loss after traumatic brain injury in female rats. Exp. Neurol. 197, 235-243.

In the paper

“which may have different prevalence in women and men”

In the paper

“Injury severity, genetic factors, and age may interact with biological sex to determine TBI outcomes.”

In the paper

“Sex differences in mitochondrial function and dynamics may be important sources of sex differences in TBI.”

In the paper

“Because larger sample size affords greater statistical power and might better represent the general population”

In the paper

“such under-representation likely has a negative impact on clinical care and limits successful drug development.”