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From Future Neurology

Traumatic Brain Injury And Gender: What Is Known
And What Is Not
Ron Hirschberg; Dorothy Weiss; Ross Zafonte
Posted: 10/07/2008; Future Neurology. 2008;3(4):483-489. © 2008 Future Medicine Ltd.
Abstract and Introduction

Abstract
This work seeks to provide a brief review of the present state of knowledge of gender
differences in traumatic brain injury and the role of sex hormones in the injury and recovery
process. A full appreciation of the extent of the laboratory and clinically important differences
remains to be defined. The role such differences will play in designing clinical trials and eventual
clinical treatment is part of an exciting future in this arena of research.

Introduction
The global incidence of traumatic brain injury (TBI) is difficult to fully assess; however,
estimations are that more than 9.5 million persons are affected. In the USA there are more than
1.4 million TBIs each year and more than 5.3 million people who live with significant disability as
a result of TBI.[1-3]

A recent report from the US CDC showed that death from TBI was 3.4-times more common for
males versus females; specifically, males were 2.3-times more likely to have sustained injury by
motor vehicle crash, 2.5-times more likely to have a TBI secondary to falls and 6.0-times more
likely to be injured via firearms.[3] The majority of TBI research does not only come from male
subjects, but data has been lacking that separates gender in analyses. Although it is true that
much of what is known in the field of brain injury medicine comes from studies with male
subjects, the gaps in our understanding of prevention, neuroprotection, secondary injury,
rehabilitation timing and therapeutics, and specific outcome remain large.

The current review aims to investigate what we have learned with respect to gender and TBI at
the levels of basic science and rehabilitation research. We discuss the differences between
males and females with respect to neuroendocrine, neurotransmitter and neuroanatomical
aspects. We review some of the relevant neuropsychiatric conditions and their respective
gender-specific research. What has been gained from animal research, human exploratory
research, and the implications for acute and chronic treatment options in humans will also be
addressed.

Sex Differences in the Brain: Impact on Neuropsychiatry

In order to fully evaluate differences between the sexes with respect to TBI, an understanding of
the neuroanatomic and neurochemical structure of the male and female brain is necessary.
Much of what we know about the morphological and chemical discrepancies in the human brain
as well as through preclinical work stems from the neuropsychiatric literature.[4]

Average human brain volumes have been calculated at 1130 cm3 and 1260 cm3 for females and
males, respectively. Although there has been some conflicting evidence over the years, for the
1
most part studies have shown women to have larger volumes of gray matter and a higher
gray:white matter ratio, whereas men have larger white matter volumes overall. It has been
shown that in males, frontal and parietal gray matter volumes correlate with IQ scores, while
female scores correlate with frontal lobe volume and, specifically, Broca's area volume.[5-9] It is
postulated that the relatively higher verbal and language skills in women and the higher visual-
spatial skills in men are associated with these differing distributions.

As for the developing brain, studies have demonstrated that young females have larger
hippocampal volumes and that young males have larger volumes in the amygdala.
[10,11]
Interestingly, estrogen concentrations have been shown to be relatively higher in the
hippocampus, whereas androgen receptors are found at higher concentrations in the amygdala.
As we age, we have learned that in males the frontal and temporal lobes lose relative volume,
as opposed to females who lose volume over time in the hippocampus and the parietal lobes.
[12,13]

The neurotransmitters serotonin and dopamine have been the most examined in terms of
predilections for female and male brain regions and overall neurotransmitter density. The
neuropsychiatric literature has demonstrated how serotonergic and dopaminergic pathways
differ between males and females, which in turn may have significant implications regarding
identification and treatment of various affective and psychotic disorders.

Overall, women have higher levels of 5-hydroxytryptamine (5-HT) in the brain and, specifically,
have a higher density of 5-HT transporter availability in the brain stem and diencephalon, as
compared with men. Men have been reported to synthesize serotonin at a faster rate than
women.[14]

The concept of differing amounts of 'dopaminergic tone' between men and women has been
addressed in several neuropsychiatric conditions, such as schizophrenia, bipolar disorder and
Parkinson's disease. It has been speculated that if females possess higher dopaminergic tone,
then they may respond better to dopaminergic medications, specifically antipsychotics or
prodopaminergic medications, such as levodopa. The dopaminergic response to amphetamine
has been shown to be elevated in females versus males, and the overall dopamine transporter
density has been found to be higher in females.[15] The cognitive sequelae following TBI indeed
involve these same neurotransmitter pathways. Therefore, it is essential to appreciate the
discrepancies among male and female physiological and pathophysiological neurochemistries.

Given gender differences in the neuroanatomy and neurochemistry of the human brain, it can
be inferred that disease or trauma to the architecture of the CNS may certainly have both
gender-specific diagnostic and treatment implications. Gestational brain development research
has revealed that although males and females are genetically quite similar, the mature brain
has already been 'shaped' by hormones, beginning in utero and spanning development.
Different sex hormones enter the brain at different times during the lifetimes of men and women,
and disease processes such as Alzheimer's, schizophrenia and anxiety disorders have shown
both predilection and severity among females versus males.[16]

After adjusting for relative female longevity, women are significantly more likely to develop
Alzheimer's disease, and 30-50% of women over 85 years of age develop symptoms of
dementia.[17] With respect to schizophrenia, younger women have been shown to respond better
to antipsychotic treatment, which may be due, in part, to higher dopaminergic tone. Women
have been consistently noted to be significantly more prone to anxiety disorders (i.e.,
generalized anxiety disorder, post-traumatic stress disorder, agoraphobia and panic disorder)
than men. Estrogens have been shown to upregulate GABA receptors, and metabolites of
progesterone have been found to be GABA-antagonists, leading to the assertion that female
hormones may in fact promote an anxiolytic state.[16,18,19]
2
Not unlike experimental studies in TBI, studies utilizing animal models of acute and chronic
stress have traditionally focused on males only. A recent review discussing the impact of gender
and age on chronic stress in animal models reported a study in which females and males
exposed to 21 days (6 h per day) of the same stress gave rise to significantly better
performance in females with respect to spatial memory, water maze proficiency and object
recognition.[20] In another study, anxiety was measured (by latency to entry into an open field),
revealing that at baseline, male rats demonstrated higher anxiety than females; however, when
exposed to the same chronic stress environment, females showed increased anxiety, whereas
males showed decreased anxiety ( Table 1 ).[20]

Table 1. Gender-based Differences in the Effects of Chronic Stress

Data Male Female

Anatomical 1260 cm3 volume
Larger volume of white
matter
Frontal and parietal gray
matter volumes correlate
with IQ scores (visual-
spatial)
Young males have larger
volumes in the amygdala
(where there are higher
concentrations of androgen
receptors)
Neurotransmitter & Synthesize serotonin at a
neurohormonal faster rate
Animal data At baseline, male rats
demonstrated higher
anxiety
Decreased anxiety when Increased anxiety when exposed to
exposed to the same the same chronic-stress
chronic-stress environment environment
1130 cm3 volume
Larger volume of gray matter,
higher gray:white matter ratio
Frontal lobe volume and Broca's
area volumes correlate with IQ
scores (verbal and language)
Young females have larger
hippocampal volumes (where there
are higher concentrations of
estrogen)
Higher levels of 5-
hydroxytryptamine (5-HT) in the
brain, and higher density of 5-HT
transporter availability in the
brainstem and diencephalon
Elevated dopaminergic response to
amphetamine
Higher overall dopamine
transporter density
Female hormones may promote
anxiolytic state
Under chronic stress, female rats
performed better in spatial memory,
water maze proficiency and object
recognition
Female sex hormones' positive
effect on brain edema, cortical

3

Natural progesterone
appears to positively affect
outcome
Differences in Outcome in Moderate & Severe TBI
lesion size and protection of the
BBB
Natural progesterone appears to
positively affect outcome

Although there is an emerging amount of work that focuses on the biochemical and hormonal
differences between the male and female brain, we continue to ask the essential question: is
there a difference in overall outcome between males and females? Overall, the majority of
earlier studies have utilized classic broad outcome measures that have generally reported
worse female outcomes; however, some more recent work has not. Data from the IMPACT
study was analyzed for Glasgow Outcome Scores at 6 months following moderate-to-severe
TBI, and found that age, race and education were all associated with outcome, and gender was
not.[21-24]

In 2000, Farace performed a meta-analysis regarding outcome and concluded that women fair
worse overall. After an extensive Medline search, including 'gender' and 'sex' as keywords, they
included a total of eight studies that had separately analyzed women and men with respect to
outcome. Most of these studies used specific symptoms at follow-up, or return-to-work status as
outcome variables. This analysis did not include age-matching criteria, which may have had an
impact on results, since female gonadal hormone circulation changes from childbearing to
postmenopausal age.[25]

More recently, injury severity with respect to gender was compared by Slewa-Younan, who
concluded that while controlling for mechanism of injury and speed of collision, males revealed
significantly lower initial Glasgow Coma Scores and longer durations of post-traumatic amnesia
than did females. Interestingly, their Glasgow Outcome Scales were the same after
rehabilitation.[26]

Ratcliff and colleagues explored this question and found that at 1 year from injury, women
showed better memory and language skills, while men showed better visual analytic skills, using
neuropsychological outcome measures. Interestingly, these results held true while controlling
for normative data (differences between men and women without TBI).[27]

The apparent gender differences with respect to injury, illness and outcome are not necessarily
unique to TBI. In 1945, Britton and Kline studied the effect of hypoxia in rats and observed that
females actually had a 40% increase in survival time than age-matched males.[28] There are
several studies that have demonstrated the decreased incidence of ischemic stroke in females,
both in human work and experimental models. Rate of survival and extent of cerebral pathology,
including neuronal loss, have been shown to be favorable in female rodents, following
experimental ischemic stroke.[29] In patients with subarachnoid hemorrhage, favorable outcome
was shown to be significantly better for females versus males at 3-month follow up, and
mortality was found to be significantly lower in one randomized clinical trial addressing the effect
of tirilizad.[30]

Preclinical Research: Examinations of Gender Differences

Neuroprotection and TBI have been studied extensively using animal models, and much of what
has been learned is that of the female sex hormones' positive effect on brain edema, cortical
lesion size and protection of the BBB.[31-35] Progesterone is produced in the brain, in neurons and
glia in females and males. Since progesterone does not have the same marked effects on

4
gender characteristics and sexual function, as does estrogen, it is particularly appealing as a
study target and possible clinical treatment option. It has been described that progesterone
reduces vasogenic and cytotoxic edema after TBI, and that natural progesterone appears to
positively affect outcome, whereas medroxyprogesterone (synthetic) may not.[36-38]Progesterone
may also inhibit inflammatory markers, including NF-κB and TNF-α.[39] VanLandingham et
al. demonstrated that progesterone and its metabolite allopregnanolone increase protein CD55
after brain injury in the rat model, inhibiting complement convertases and, therefore, the
inflammatory cascade.[40]

It has been suggested that the temporal course post-traumatic injury of edema and cortical
lesion size may have more clinically relevant implications on eventual outcome.[34] Jones et
al. demonstrated that in male mice the above neuroprotective effects remained significant when
administered progesterone, in that their cognitive ability was enhanced on spatial tasks using
the Morris water maze (MWM). Interestingly, in this particular model, male mice given
progesterone showed no decrease in cerebral edema, as did their female counterparts,
suggesting that neuroprotection with sex hormones may be independent of edema and
inflammatory response.[35]

Given the growing body of literature on the potential advantages of progesterone post-TBI,
investigators have been eager to support this concept in preclinical trials. O'Connor et
al. recently examined the effects of administration of progesterone to injured rats using a 'diffuse
model' (acceleration-based injury) to mimic axonal pathology in humans. Notably, observed
functional tasks were similar in injured males and injured ovariectomized females, and when
given progesterone postinjury, motor and cognitive tasks were shown to be significantly
improved in male and ovariectomized female rats, as compared with controls. In addition,
markers of axonal injury were reduced in males and ovariectomized females when given
progesterone versus controls.[41] Roof and Hall have shown that in the condition of
'pseudopregnancy' or high levels of progesterone, female rats demonstrated no signs of
cerebral edema using the contusion model. In addition, when male rats were given
progesterone prior to impact, their levels of cerebral edema were reduced and functional skills
were increased.[42,43]

The modulation of female gonadal hormones may have significant effects on neurotransmitter
activity and expression. Wagneret al. looked at the effect of methylphenidate treatment for 20
days postcortical impact in the rat TBI model. Without treatment, female rats demonstrated
better motor tasks (beam balance and walking) than did males. When treated with
methylphenidate, only the male rats showed increased performance as compared with those
not receiving treatment, with respect to memory and retention of information.[44] Rogers and
Wagner suggest that TBI itself may trigger endogenous hormonal mechanisms that attenuate
damage incurred by the secondary injury cascade.[45] For example, it has been proposed that
progesterone acts as an enhancer of GABA activity, further balancing brain neurochemistry
while excitatory influences are overactive postinjury. We have also learned from animal
research that there are potential nonhormonal factors that seemingly impact recovery and
performance with respect to gender. A recent study sought to compare standard versus
'environmentally-enriched housing environments' postcortical injury in rats. Although
environmental performance did not affect motor performance, it had a significant impact on
spatial memory performance in males over females.[46]

Other hormones have also been investigated as neuroprotectants. Estrogen has been
described as a blood vessel modulator via nitric oxide pathways, contributing to protection
against vascular-induced injury. It may also provide anti-oxidant properties, reduce amyloid ß
production and resulting neurotoxicity, and increase antiapoptotic factor bcl-2.[42] Estrogen may
play a similar inhibitory role as progesterone, acting as an antiglutaminergic agent, thereby
reducing secondary brain injury. Emerson et al. demonstrated that prophylactic 17ß-estradiol
5
administered to rats 4 h prior to fluid percussion TBI resulted in a protective effect in males but
worsened mortality in females.[47] More recent work from Roof and Hall showed that female rats
given 17ß-estradiol for 2 weeks prior to injury fared better than males given the same treatment
following impact-acceleration injury.[42]

Effects of testosterone on brain pathology have been explored less. In male rats, castration has
been shown to decrease ischemia-reperfusion injury in animal stroke models, inferring that
lower levels of testosterone may in fact be neuroprotective.[48] In a cortical ischemic model,
Yang et al. demonstrated the deleterious effect of testosterone on ischemic lesion volume and
that testosterone was associated with increased glutamate toxicity. Acute depletion of
testosterone just prior to experimental injury actually showed a time-dependent improvement in
lesion size versus controls. Of note, in the same study it was demonstrated that 17ß-estradiol
ameliorated glutamate toxicity using the same model.[49]Dehydroepiandrosterone sulfate
(DHEAS) has also been shown to play a neuroprotective role after brain injury. Hoffman et
al.write that DHEAS has been implicated in promotion of neuronal migration and synapse
formation,[50] thereby contributing to recovery after brain injury.

We have learned that hormones play a variety of neurochemical roles post-TBI, and it remains
unclear as to the importance of the relationship between the timing of injury and timing of the
natural cycling of hormones. Interestingly, a recent review by Stein discussed data suggesting
that fluctuations in hormonal levels in females may actually impact recovery from brain injury.
[37]
However, an earlier study evaluated preinjury estrous stage in female rats and suggested
that the presence of endogenous hormones, rather than the actual state of those hormones at
the time of injury, may underlie overall neuroprotection for females post-TBI.[51]

Human Exploratory Research

Gender and the neuroprotective effects of female gonadal steroids have been well studied in
experimental TBI; however, more recent work in gender differences in cerebrospinal fluid (CSF)
markers has provided validation of these effects in humans. Wagner et al. showed that during
the first 3 days following TBI, markers of secondary brain injury and oxidative damage were
increased temporally in males versus females. A subsequent study specifically looked at CSF
excitotoxic levels of glutamate and lactate/pyruvate, and determined that males had higher
postinjury levels of these secondary brain injury markers than did females.[52,53]

The use of moderate hypothermia following severe TBI did not demonstrate efficacy with
respect to functional outcome, in a multicenter clinical trial in 2001. An earlier study, however,
did show a significant improvement in Glasgow Outcome Scale scores at 3 and 6 months from
injury in those treated with hypothermia versus those treated with normothermia, in a subset of
individuals with initial Glasgow Coma Scale scores of 5 through 7.[54,55]

The effect of hypothermia on attenuation of CSF markers of secondary brain injury has been the
focus of several studies, and hypothermia's relationship with post-TBI glutamate levels,
regardless of gender, have demonstrated conflicting results. Evaluating hypothermia's effects
with respect to gender in human TBI was more recently reported by Wagner and colleagues. It
was shown that post-TBI levels of CSF glutamate and lactate/pyruvate were not linked to
gender. However, the effect of hypothermia on glutamate production post TBI was gender-
specific, in that males treated with hypothermia had decreased glutamate levels versus males
treated with normothermia, and that females did not demonstrate this relationship.[53]

In humans, the first trial using progesterone was recently reported by Wright et al. This pilot,
randomized, double-blind, placebo-controlled trial sought to prove the safety of human
progesterone use in moderate-to-severe TBI and assess functional outcome benefit. Although
its sample size was relatively low, it did show lower mortality at 30 days in patients receiving
6
progesterone versus placebo. In addition, for patients with moderate TBI, 30-day follow-up
revealed improved Glasgow Outcome Scale-extended scores in the treatment group compared
with those in the control group, with 1-year follow-up pending at the time of this review ( Table
2 ).[56]

Table 2. Outcome Differences Following Progesterone use in Traumatic Brain

Injury

Male
Lower initial Glasgow Coma Scores and
longer durations of post-traumatic amnesia
Glasgow Outcome Scale scores were the
same after rehabilitation
1 year from injury, better visual analytic skills
Future Perspective
Female
Women fair worse overall
Glasgow Outcome Scale scores were
the same after rehabilitation
1 year from injury, better memory and
language skills

The data presented in this review is a brief summary of the literature. What is evident is that
important differences exist between genders in both laboratory and animal models and in early
clinical testing. It will be important to determine the mechanism of the neuroprotective and
neurofacilitory differences between genders as well as to understand the psychosocial factors
that impact on the neurobiologic aspects of injury. Future investigators need to understand what
aspects of gender-based differences need to be accounted for in clinical trials and how
neurosex hormones can be manipulated to enhance the recovery process.

Sidebar: Executive Summary

Sex Differences in the Brain: Impact on Neuropsychiatry

• Gender-based brain volume and neurotransmitter differences exist and may have a role
in both behavioral and neurorecovery-related differences that have been observed.

Differences in Outcome in Moderate & Severe Traumatic Brain Injury

• Gender-based differences in outcomes have been reported, although the findings in

humans are inconclusive and suggest neuroendocrine, biomechanical and sociologic
factors may contribute.

Preclinical Research: Examinations of Gender Differences

• Laboratory research has suggested a protective role for progesterone, and other
neurosteroids may be involved in the protective and recovery processes as well.

Human Exploratory Research

• Human studies have demonstrated gender-based differences in biomarker response to

injury as well as treatment intervention. A recent intervention trial employing
progesterone as a neuroprotective agent is promising.

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Authors and Disclosures

Ron Hirschberg, Dorothy Weiss, Ross Zafonte, Harvard Medical School, The Department of
Physical Medicine & Rehabilitation, Spaulding Rehabilitation Hospital, The Massachusetts
General Hospital, Boston, MA

Reprint Address
Ross Zafonte, Harvard Medical School, Spaulding Rehabilitation Hospital, The Massachusetts General
Hospital, 125 Nashua Street, Boston, MA 02214. E-mail: rzafonte@partners.org .
Future Neurology. 2008;3(4):483-489. © 2008 Future Medicine Ltd.

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