Former NFL players who received a concussion while playing are more likely to report low testosterone and erectile dysfunction

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Former professional football players who have experienced concussion symptoms, including loss of consciousness, disorientation or nausea after a head injury, are more likely to report low testosterone and erectile dysfunction (ED), according to research published Aug. 26 in JAMA Neurology.

The research – based on a survey of more than 3,400 former NFL players representing the largest study cohort of former professional football players to date – was conducted by investigators at the Harvard T.H. Chan School of Public Health and Harvard Medical School as part of the ongoing Football Players Health Study at Harvard University, a research program that encompasses a constellation of studies designed to evaluate various aspects of players’ health across their lifespans.

The researchers caution that their findings are observational – based on self-reported concussion symptoms and indirect measures of ED and low testosterone.

The results do not prove a cause-effect link between concussion and ED, nor do they explain exactly how head trauma might precipitate the onset of ED, the investigators noted.

However, the findings do reveal an intriguing and powerful link between history of concussions and hormonal and sexual dysfunction, regardless of player age.

Notably, the ED risk persisted even when researchers accounted for other possible causes such as diabetes, heart disease or sleep apnea, for example.

Taken together, these findings warrant further study to tease out the precise mechanism behind it.

One possible explanation, the research team said, could be injury to the brain’s pituitary gland that sparks a cascade of hormonal changes culminating in diminished testosterone and ED.

This biological mechanism has emerged as a plausible explanation in earlier studies that echo the current findings, such as reports of higher ED prevalence and neurohormonal dysfunction among people with head trauma and traumatic brain injury, including military veterans and civilians with head injuries.

The new findings also suggest that sleep apnea and use of prescription pain medication contribute to low testosterone and ED. It remains unclear whether they do so independently, as consequences of head injury or both, the researchers said.

Sexual function is not only a critical marker of overall health but also central to overall well-being, the researchers note. Understanding the mechanisms behind the possible downstream effects of head injury, they said, can inform treatments and preventive strategies.

“Former players with ED may be relieved to know that concussions sustained during their NFL careers may be contributing to a condition that is both common and treatable,” said study lead author Rachel Grashow, a researcher at the Harvard T.H. Chan School of Public Health.

The results are based on a survey of 3,409 former NFL players, average age 52 years (age range 24 to 89), conducted between 2015 and 2017.

Participants were asked to report how often blows to the head or neck caused them to feel dizzy, nauseated or disoriented, or to experience headaches, loss of consciousness or vision disturbances – all markers of concussion. Responders were grouped in four categories by number of concussive symptoms.

Next, the former players were asked whether a clinician had recommended medication for either low testosterone or ED, and whether they were currently taking such medications.

Men who reported the highest number of concussion symptoms were two and a half times more likely to report receiving either a recommendation for medication or to be currently taking medication for low testosterone, compared to men who reported the fewest concussion symptoms.

Men with the most concussion symptoms were nearly two times more likely to report receiving a recommendation to take ED medication or to be currently taking ED medication than those reporting the fewest symptoms. Players who reported losing consciousness following head injury had an elevated risk for ED even in the absence of other concussion-related symptoms.

Notably, even former players with relatively few concussion symptoms had an elevated risk for low testosterone, a finding that suggests there may be no safe threshold for head trauma, the team said.

Of all participants, 18 percent reported low testosterone and nearly 23 percent reported ED. Slightly less than 10 percent of participants reported both.

As expected, individuals with cardiovascular disease, diabetes, sleep apnea and depression, as well as those taking prescription pain medication – all of which are known to affect sexual health – were more likely to report low testosterone levels and ED.

Yet, the link between concussion history and low testosterone levels and ED persisted even after researchers accounted for these other conditions.

Risultati immagini per brain concussion

The researchers caution that their findings are observational – based on self-reported concussion symptoms and indirect measures of ED and low testosterone. The image is credited to Harvard.

The link between history of concussion and ED was present among both the older and the younger players—those under age 50 in this case – the analysis showed, and it persisted over time.

“We found the same association of concussions with ED among both younger and older men in the study, and we found the same risk of ED among men who had last played twenty years ago,” said study senior author Andrea Roberts, a researcher at the Harvard T.H. Chan School of Public Health.

“These findings suggest that increased risk of ED following head injury may occur at relatively young ages and may linger for decades thereafter.”

Given that ED is both fairly common and easily treatable, those who experience symptoms are encouraged to report them to their physicians, the researchers said.

Importantly, prompt evaluation of ED is critical because it can signal the presence of other conditions, including heart disease and diabetes.

The findings also suggest that it may be important for clinicians to assess all patients with concussion history for the presence of neurohormonal changes.

“ED is a fact of life for many men,” said Herman Taylor, director of player engagement and education and director of the Cardiovascular Research Institute at Morehouse School of Medicine.

“Anyone with symptoms should seek clinical attention and thorough evaluation, particularly since ED can be fueled by cardiovascular and metabolic disorders. The good news is that this is a treatable condition.”

Pascual-Leone was partly supported by the Sidney R. Baer Jr. Foundation, the National Institutes of Health (R01MH100186, R21AG051846, R01MH111875, R01MH115949, R01 MH117063, R24AG06142 and P01 AG031720), the National Science Foundation, DARPA, the Football Players Health Study at Harvard University and Harvard Catalyst The Harvard Clinical and Translational Science Center (NCRR and the NCATS NIH, UL1 RR025758).

He serves on the scientific advisory boards for Neosync, Neuronix, Starlab Neuroscience, Neuroelectrics, Magstim Inc., Constant Therapy and Cognito, and is listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation with electroencephalography and magnetic resonance imaging.

Baggish has received funding from the National Heart, Lung, and Blood Institute, the National Football League Players Association, the American Heart Association and the American Society of Echocardiography and receives compensation for his role as team cardiologist from US Soccer, US Rowing, the New England Patriots, the Boston Bruins, the New England Revolution and Harvard University.

He also serves on the editorial board for Circulationand as an associate editor for Medicine Science Sports & Exercise.

Zafonte received royalties from Oakstone for authorship of an educational CD; Demos Medical Publishing for serving as co-editor of the textbook Brain Injury Medicine. He serves on the scientific advisory boards of Myomo, Oxeia Biopharmaceuticals, ElMINDA and BioDirection. Zafonte evaluates patients in the MGH Brain and Body-TRUST Program, funded by the NFL Players Association.


Traumatic brain injury (TBI) is defined as an alteration in brain function or other evidence of brain pathology caused by an external force (1). The clinical terms regarding severity and phase of TBI are described in Table 1.

TBI is a well-known public health problem worldwide and is a leading cause of death and disability. In the United States, each year 235 000 Americans are hospitalized because of nonfatal TBI, 1.1 million are treated and released from an emergency department, and approximately 50 000 die (2).

It has also been reported that 124 000 (43.1%) Americans discharged with TBI after acute hospitalizations develop TBI-related long-term disability (3). In Europe, the aggregate hospitalized plus fatal TBI incidence rate is approximately 235 per 100 000, and the case fatality rate is approximately 11 per 100 (4).

The TBI severity ratio of hospitalized patients was approximately 22:1.5:1 for mild vs moderate vs severe cases, respectively (4). In another study from Christchurch, New Zealand, the annual incidence of TBI was reported to range from 1100 per 100 000 to 2360 per 100 000, and by 25 years of age, 31.6% of the population had experienced at least one TBI (5).

The most frequent causes of TBI include: motor vehicle accidents (the leading cause, accounting for nearly 50% of causes), falls, acts of violence, sports-related head traumas (eg, in swimming, hockey, soccer, football), combative sports (eg, boxing, kickboxing), and blast-related injuries (67).

Table 1

Descriptions of Commonly Used Clinical Terms of TBI

Severity 
    The Glasgow Coma Scale (GCS) is the most commonly used clinical tool to evaluate the severity of head trauma. It assesses eye opening, verbal, and motor responses on a scale ranging from 3 to 15 (279). 
        Mild TBI: GCS of 13–15 
        Moderate TBI: GCS of 9–12 
        Severe TBI: GCS of 3–8 
    Phase 
        Acute phase: generally accepted as the first 10 or 14 days after TBI 
        Chronic phase: defined as at least 3 months after TBI 

More than 90 years ago, in 1918, neuroendocrine dysfunction due to TBI was described for the first time (8). After that first case, only three additional cases (911) were reported until 1940, two in France (1921 and 1927) and one in the United Kingdom (1922).

These cases involved work injury, an explosion and fall, and a traffic accident, respectively. Only case reports and small case series were reported until 2000; however, neuroendocrine dysfunction after TBI has been extensively investigated since then.

Two cornerstone papers (1213) drew attention to TBI-induced pituitary dysfunction and stimulated new studies. A high prevalence of hypopituitarism has been reported in most of the studies in the literature. Although the frequency of hypopituitarism after TBI varies widely in published reports, this finding at most reports a range of 15–50% of the patients with TBI (1415).

Historically, most of the early studies were cross-sectional or with short-term follow- up. Recently, a long-term (5 y) prospective study was performed in 25 TBI patients (16).

At the fifth year, the prevalence of permanent anterior pituitary hormone deficiency was 28, 4, and 4% for GH, gonadotropin, and ACTH, respectively.

This is the only 5-year, prospective, single-center study, and throughout the follow-up period, the same diagnostic tests and laboratory assays were performed.

The evaluation of quite a low number of patients was the major weakness of the study (16). Recently, a group of experts reviewed the literature on TBI-induced hypopituitarism and concluded that it is often not appreciated or diagnosed and that the medical community is not adequately informed about the importance of the problem (17).

Our goal in the present review is to update the current data regarding the epidemiology, diagnosis, pathophysiology, and consequences of pituitary hormone deficiencies after TBI, the screening and follow-up strategies, and the treatment of TBI-induced hypopituitarism.

Prevalence of Chronic Posttraumatic Anterior Pituitary Dysfunction in Adults

TBI was recognized as a potential cause of hypopituitarism after a review summarized the literature on 367 cases of posttraumatic hypopituitarism (12). In addition, two preliminary studies reported a high prevalence of hypopituitarism after TBI (1318).

Following these reports, diagnostic studies were launched to further assess the prevalence of hypopituitarism after TBI.

In 2007, a systematic review was performed to summarize the literature, suggesting that neuroendocrine dysfunction was common after TBI (14). Other studies questioned these results by reporting a lower prevalence of hypopituitarism after brain damage (28 vs 5% [19] to 30% [20]).

Additional studies emphasized the role of endocrine tests and cutoffs for determining the prevalence of TBI-related hypopituitarism (19).

Klose et al (21) evaluated GH secretion in 439 TBI patients (median, 2.5 y after TBI) and 124 healthy controls using various tests, cutoffs, and laboratory assays. The prevalence of GH deficiency (GHD) was different using local vs guideline cutoffs, insulin tolerance test (ITT), pyridostigmine (PD)-GHRH test, or GHRH plus arginine (GHRH+ARG) test, single vs repeated testing, and two different GH assays.

The prevalence of GHD was found to be lower by local than by guideline cutoffs (12 vs 19% [PD-GHRH/GHRH+ARG, P < .001]; 4.5 vs 5% [ITT, P = .9]) and by ITT than by PD-GHRH/GHRH+ARG (P = .006 [local cutoffs]; P < .001 [guideline cutoffs]). Only 1% of patients had GHD according to two tests. GH assessment by Immulite or Isys assay caused no significant diagnostic differences. Moreover, they showed that a substantial number of false-positive results were found in the control group.

The limitations of this study were that the PD-GHRH stimulation test is not a commonly used test in the diagnosis of adult GHD (21), and it is not well-standardized (22).

For this reason, it is not appropriate to confirm the results obtained from the ITT with a less sensitive test.

The GHRH+ARG test, which has been more commonly used and is widely available (22), was only used in patients who had contraindications to other testing. Unavoidable problems due to the multicenter design of the study were also present, and importantly, most of the patients in their cohort had mild TBI.

Given the divergent results in the literature, we conducted a systematic review on the prevalence of hypopituitarism (at least 3 mo) after TBI.

Additionally, we analyzed the effects of excluding less severely affected patients, using repeated testing, and the concomitant prevalence of abnormal endocrine results in healthy controls.

Hypopituitarism due to Sports-Related Chronic Repetitive Head Trauma

A. Definition of sports-related traumatic brain injury

Sports, including contact/combative sports, are common around the world, especially among the younger generation. Sports-related competitions/championships at both national and international levels are among the most attractive and popular events worldwide and generate attendance by an enormous body of people.

Consequently, there are a great number of professional and amateur athletes around the world participating in a wide variety of sports that appeal to the masses.

Despite the frequency and well-known health outcomes, trauma due to sports is not generally taken into account as a cause of TBI in most epidemiological studies (7).

Sports-related TBI is a common public health problem worldwide that is associated with increased morbidity and may cause mortality.

The annual frequency of sports-related TBI has been reported as between 1.6 million and 3.8 million in the United States (33). In another study, 21% of all TBIs, which equates to an incidence rate of 170 per 100 000, were identified as resulting from a sports-related activity. Most sports-related injuries were classified as mild TBI (46%) with a high risk of complications, including mainly cognitive dysfunction (34). Contact/combative sports including boxing, kickboxing, soccer, football, ice hockey, and rugby are the most common types of sports that may result in chronic TBI, most often as a result of closed head injury.

Concussion is a well-known and most typical injury associated with sports, particularly combative sports including boxing, football and ice hockey. Concussion, which occurs after the transmission of direct or indirect impulsive forces to the head, is characterized by the rapid onset of short-lived impairment of neurological function that resolves spontaneously (3335). Cerebral concussion may develop after only one simple punch or as accumulated damage from multiple punches; cognitive dysfunction is reported in most boxers (36).

Sports-related TBI is also divided into two types: acute and chronic. Acute head trauma in an athlete is similar to other types of closed head trauma, such as from a fall or a traffic accident, in terms of the type of trauma and consequences of trauma.

Chronic TBI includes multiple traumas (recurrent concussion) or repetitive traumas. Multiple trauma is characterized by multiple episodes of trauma that are not regularly repetitive and that happen unexpectedly at any time during a sporting activity. Boxing and kickboxing are characterized by chronic repetitive traumas. The total number of matches may be up to 850 in boxers and 4800 in kickboxers (3738).

Boxing, a very common combative sport that is practiced worldwide, is associated with chronic, repetitive head trauma and may be responsible for TBI (3940).

Chronic TBI has been reported in 20% of professional boxers (4142). Repetitive head trauma in boxers causes brain injury, as shown by alteration in circulating brain markers after fighting. For example, in a study by Zetterberg et al (43), neuron-specific enolase (NSE), a glycolytic enzyme expressed selectively in neurons, was significantly increased after boxing when compared to normal controls. Sustained, increased levels of neuron-specific enolase in amateur boxers suggest subacute brain injury due to repetitive head blows.

B. Pituitary dysfunction due to sports-related brain injury

Although the relationship between sports injuries and brain trauma has been suggested, neuroendocrine dysfunction has not been routinely investigated until recently (7).

A study in amateur boxers in 2004 (37) evaluated pituitary function in 11 actively competing or retired male amateur boxers compared with those of healthy nonboxing controls. Based on the GHRH+GHRP-6 test, isolated GHD was diagnosed in 45% of the boxers, and the mean IGF-1 levels in boxers were significantly lower than in the control group.

Similarly, peak GH levels after GHRH+GHRP-6 stimulation correlated negatively with boxing duration and number of bouts.

In an analysis of kickboxing in which kicking, punching, and, under some rules, kneeing, and elbowing are permitted (44), the International Kickboxing Federation estimated that about 1 million participants around the world are involved in kickboxing (45). Like boxing, kickboxing is characterized by chronic repetitive head trauma, and the head is one of the most frequently injured organs among amateur and professional kickboxers (4445). Pituitary function was investigated by measuring basal hormone levels, GH responses to GHRH+GHRP-6, GH and cortisol responses to glucagon stimulation tests, and cortisol responses to ACTH stimulation test in 22 amateur kickboxers compared to 22 healthy controls. Kickboxers had a higher incidence of GH and ACTH deficiencies: 22.7 and 9.1%, respectively. Of the patients, 27.3% had at least one anterior pituitary hormone deficiency. Therefore, kickboxing is a newly appreciated cause of TBI, and kickboxers are at increased risk of hypopituitarism, particularly isolated GH deficiency (38).

Tanriverdi et al (46) measured body composition variables, pituitary volume, and pituitary functions in 61 actively competing (n = 44) or retired boxers (n = 17). Nine of the 61 boxers (15%; eight retired and one actively competing) had GHD, and five of the 61 boxers (8%) had ACTH deficiency. In other words, eight of the 17 retired boxers (47%) had GHD. Interestingly, pituitary volume in GH-deficient boxers was significantly lower than pituitary volume in GH-normal boxers.

Body composition variables, including fat ratio, fat mass, abdominal fat ratio, abdominal fat mass, body mass index (BMI), and waist circumference, were significantly higher in boxers with GHD when compared with GH-normal boxers.

This study suggests that the routine screening of pituitary functions is required particularly in retired boxers (46). In another study of anthropometric and body composition variables, serum IGF-1 and leptin levels were measured in active and retired amateur boxers and sex-matched, healthy, nonboxing controls. IGF-1 levels were found to be significantly lower in retired boxers than in actively competing young and adult competitors. This study clearly shows that the low IGF-1 levels, which were negatively correlated with body composition variables in retired boxers, could be responsible for abnormal anthropometric and body composition parameters (47).

It is important to mention that, although the studies suggest that boxers with GHD have increased cardiovascular risk factors, long-term or prospective studies on cardiovascular events have not been performed.

Recently, investigators have evaluated the risk of TBI in football players. Kelly et al (48) prospectively studied a cohort of retired US professional football players (from the National Football League) with relatively low quality of life as measured by validated questionnaires aiming to evaluate the rate of pituitary and associated sexual and metabolic dysfunction. The prevalence of hypopituitarism and metabolic syndrome was relatively common (23.5 and 50%, respectively) and could have contributed to their poor quality of life. GHD (19.1%) and hypogonadism (8.8%) were found to be the most common pituitary dysfunction after repetitive sports-related concussion in football players (48). The authors suggest that hypopituitarism and metabolic syndrome could be considered as important factors in the poor quality of life and general health of retired football players. To understand the causative link between sports-related head trauma and hypopituitarism, further studies in athletes sustaining repetitive head injury are needed.

C. Prevention of sports-related neuroendocrine dysfunction

It is predicted that headgear can protect the brain, including the hypothalamo-pituitary region, from head trauma, but no study to assess hypothalamo-pituitary damage has been conducted in athletes, such as boxers or kickboxers, who are subjected to chronic repetitive head trauma. At the present time, the wearing of headgear during both training and championships is mandatory in Turkey, and it has been so for 20 years. Professional boxing is permitted in some European countries and the United States, and boxers do not need to wear headgear. To develop protective devices, injury mechanisms need to be identified. Although an instrumented mouth guard for measuring head kinematics during impact was developed and tested in a recent study, hypothalamo-pituitary damage was not taken into account in the development of this kind of device (49). The crucially important issue is the education of athletes, trainers, and referees in terms of awareness of hypothalamo-pituitary dysfunction related to sports. For this reason, the medical community and media should be informed about sports-related pituitary dysfunction and should be asked to deal with this issue as a matter of importance. Additionally, it has been recommended that the sponsors of sports programs should design and maintain an injury-prevention program (50).

In summary, boxing and kickboxing are novel causes of hypopituitarism. Therefore, boxers and kickboxers are at risk of hypopituitarism. Isolated GHD is the most common pituitary dysfunction. Whether or not the active boxer or kickboxer with severe GHD should receive GH replacement therapy remains an important question to be answered. Because GH has been used illegally as a doping agent by active athletes, how GH abuse might be prevented in a GH-deficient athlete is another question to be addressed.

Pituitary Dysfunction and Cognition After TBI

A. Cognitive impairment after TBI: what is the contribution of pituitary dysfunction?

Cognitive dysfunction can be an enormous problem after TBI. The Institute of Medicine’s monograph, Gulf War and Health, states: “Neurocognitive impairments result in a host of difficulties in people who sustain severe TBI, ranging from attention, memory, information processing speed, and executive functions to even more robust functions, such as language and visuospatial constructional skills” (51). Such deficits can severely impact an individual’s ability to return to an active, independent role in society. Most strategies for the treatment of these deficits have focused on treating the acute injury with neuroprotective agents (5253). Cognitive interventions for individuals with chronic TBI have been only marginally successful (54).

The cognitive manifestations of hormone deficiencies can be quite obvious, or incredibly subtle. The consequences of these deficiencies may be minor, or they may keep the individual from functioning independently in society, and these deficiencies may be masked by what has been previously attributed to the intrinsic signs and symptoms of the TBI itself. The diagnosis and treatment of posttraumatic hypopituitarism may, therefore, play a significant role in the cognitive recovery from a brain injury. The common cognitive and psychological issues after TBI are listed in Table 5.

Table 5

Common Cognitive/Psychological Issues After TBI (282283)

Language 
Information processing speed 
Depression 
Irritability 
Decision making 
Memory 
Attention: attention span, divided attention 
Alertness 
Executive function: planning, organizing, sequencing, problem solving, inhibition, multi-tasking, impulse control, self-monitoring, judgment 

1. Thyroid hormone

Although the literature on the cognitive, psychological, and psychiatric effects of abnormal thyroid function after TBI is sparse, a great deal has been written about the effects of thyroid dysfunction and replacement therapy in general. Hypothyroid patients typically demonstrate the types of deficits so commonly seen after TBI, such as in executive functioning, speed of information processing, and aspects of memory, predominantly short-term memory (55).

Evidence from animal models suggests a possible mechanism linking thyroid function to cognition as well as the positive effects of thyroid hormone replacement on cognition after brain injury. The data suggest that thyroid hormone regulates neurogenesis in the rat hippocampus, providing a logical role for the thyroid hormone in learning and memory (56). Smith et al (57) administered either T4 or a placebo to rats before they learned a water maze. T4 was administered either subchronically (every day for 4 d) or chronically (every third day for 28 d). A cognitive deficit was then induced in half of the rats with scopolamine. Both treatment regimens were found to facilitate the initial learning of the spatial task and to mitigate the deleterious effects of scopolamine.

The extent to which thyroid replacement improves cognitive, psychological, and psychiatric symptoms is somewhat unclear and may be dependent upon the severity of hypothyroidism before treatment (eg, subclinical vs primary hypothyroidism) (58). Clearly, the common cognitive symptoms after a TBI are quite similar to the cognitive symptoms of hypothyroidism. Because the screening and treatment of hypothyroidism are relatively inexpensive, they should be strongly considered in all patients who have these symptoms after TBI; however, there are no clear data regarding thyroid hormone replacement and cognitive outcomes in TBI patients.

2. Cortisol

Given the role of cortisol as a stress hormone, a relationship between cortisol levels and psychiatric symptoms (particularly symptoms of anxiety) seems tenable. In fact, there is evidence in the literature of a complex relationship among postinjury cortisol levels, injury severity, and the development of anxiety. Tanriverdi et al (59) measured pituitary functions within 24 hours of trauma in a sample of 104 patients with TBI. They found that there was a positive relationship between cortisol levels and the GCS: the less severe injuries were associated with higher cortisol levels. Flesher et al (60) examined the relationship among serum cortisol levels, amnesia, and the development of posttraumatic stress disorder (PTSD) symptoms at 1 month in 70 motor vehicle accident victims. The amnesic patients (ie, those who could not identify events shortly before, during, or shortly after the crash) demonstrated lower norepinephrine/cortisol ratios, were less likely to meet criteria for PTSD, and displayed fewer symptoms of PTSD than those who were not amnesic. Taken together, the results of these two studies suggest that factors associated with injury severity are antagonistic to an elevated cortisol response. It is possible that cortisol response is related to stressful recollections of the incident that caused the injury. Factors such as loss of consciousness and posttraumatic amnesia may prevent awareness of the injury and its potential tragic consequences, thus precluding an associated stress response.

3. Gonadotropins

The results of T supplementation in hypogonadal males, as well as in normal healthy males, have shown some improvement in some domains of memory (6162); however, studies on cognitive improvement after estrogen supplementation in females have yielded conflicting results (6364). Of the individuals who have sustained TBI, those with lower T levels also appear to have an increased risk for Alzheimer’s disease, which makes the connection between sex hormones and brain injury even more intriguing (65).

Presently, the issue of cognitive changes with sex hormone supplementation or replacement remains unresolved (66). Additionally, there are no clear data regarding the effects of sex hormone replacement on cognitive outcomes in patients with TBI-induced gonadotropin deficiency. Nevertheless, screening and appropriate replacement should be strongly considered in individuals who remain symptomatic after a TBI.

4. Growth hormone: cognitive impact of posttraumatic GHD

The mechanism by which GH may affect cognition is not well understood. GH appears to affect cognitive functioning by enhancing excitatory synaptic transmission through the N-methyl-D-aspartate receptors in the hippocampus (67). GH also modulates brain neurotransmitters (68) and may play a role in recovery from TBI. After an injury to the brain, IGF-1 has also been found to increase progenitor cell proliferation and new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus (69). There are presently only a small (but growing) number of reports on the cognitive effects of GHD after TBI. Elucidation of the independent effects of GHD on cognition may be found in GH-deficient individuals from other etiologies. In fact, GHD has been demonstrated to interfere with cognitive functioning in individuals with nontraumatic conditions (70).

Greater cognitive dysfunction has been reported in patients with TBI who have GHD compared to those with normal GH levels (71). Kelly et al (71) evaluated neurobehavioral and quality of life issues in 44 patients with TBI 6 to 9 months after injury. Compared to individuals with normal pituitary function, those with deficits of the GH axis had higher rates of at least one marker of depression, as well as reduced quality of life in the domains of general health, physical health, emotional health, pain, energy, and fatigue. The authors noted a weak trend toward the GH-deficient/-insufficient group having a more severe injury as seen on computed tomography (CT) scans. Tanriverdi et al (72) investigated the relationship between the GH-IGF-1 axis and cognitive performance in boxers and kickboxers by using neuropsychological tests, including the Mini-Mental State Examination, Quality of Life Assessment of GH Deficiency in Adults, and P300 auditory event-related potentials, which is an electrophysiological measure of updating of working memory content and attention. Consistent with impaired cognitive performance, P300 amplitudes were found to be significantly lower in GH-deficient boxers and kickboxers when compared with GH-sufficient boxers and kickboxers and healthy controls (72). An important question, however, is whether this observation reflects the specific effects of GHD or is simply a reflection of injury severity. León-Carrión et al (73) examined emotional and cognitive functioning in 22 patients with severe TBI: 11 with isolated GHD, and 11 without pituitary deficiencies. The GH-deficient group showed greater deficits in simple attention, more intrusions and repetitions on a memory task, increased reaction time, and greater emotional disruption. The results were interpreted as supporting the theory that some deficits after TBI may be the direct result of GHD, rather than being attributable more generally to the brain injury, per se. These results must be interpreted cautiously, however, because there was no indication that injury severity was similar across groups.

The effects of GH replacement on cognitive function will be discussed in the treatment section (Section IX.B).

In summary, there is a rapidly growing body of literature suggesting that hypopituitarism after TBI indeed has a negative impact on cognition. Although growing at a more moderate pace, the body of literature suggests that treatment of posttraumatic hypopituitarism has a positive effect on the cognitive problems associated with TBI.

Metabolic Consequences of Posttraumatic Hypopituitarism

Hypopituitarism, in general, and GHD, in particular, are associated with a number of metabolic alterations (7479). Consequently, it is feasible that TBI patients with neuroendocrine dysfunction may have metabolic alterations; however, few studies have evaluated these issues, including changes in body composition and BMI, lipid profile, glucose metabolism, and hypertension (46488081).

Klose et al (80) evaluated prospectively (3–12 mo after TBI) the patients who had TBI due to acute road accidents, whereas Tanriverdi et al (46) investigated a population of amateur boxers who were chronically exposed to head trauma. Both studies showed alterations in lipid profile and body composition with an increase in BMI in their subjects. The authors attributed the greatest responsibility for the impairment in body composition and lipid profile to GHD “per se,” which is in agreement with previous studies on “classical” GH-deficient patients not receiving GH replacement therapy (80). Altered body composition, insulin resistance, hypertension, unfavorable lipid profile, endothelial dysfunction and atherosclerosis have been found in several studies on patients with long-term GHD (7476778287). In fact, the cardiovascular risk in patients with hypopituitarism without any GH treatment was the main reason that prompted researchers also to propose this substitutive therapy in adults (88). More recently, Prodam et al (81), in a cross-sectional retrospective study in a tertiary care endocrinology center, confirmed that TBI patients who developed hypopituitarism had a worse metabolic profile than TBI patients who did not, particularly in terms of altered glucose levels, insulin resistance, and dyslipidemia, independent of the BMI of the patients (Table 6). The authors confirmed previous data on a tendency toward an altered lipid profile in TBI subjects with hypopituitarism with elevated triglycerides, but similar high-density lipoprotein (HDL), low-density lipoprotein, and total cholesterol in both populations. Low HDL-cholesterol was shown in classical hypopituitarism subjects with respect to controls chosen in obese subjects without hypopituitarism (75). It should be taken into account that HDL cholesterol is mainly influenced by physical activity (89), and physical limitations and prolonged recovery are specific for TBI patients. The second finding is the high prevalence of fasting or postchallenge glucose alterations. This is in line with other reports on “classical” hypopituitarism (757990), a condition marked by higher insulin resistance. The pathophysiological mechanism of diabetes and insulin resistance in patients with hypopituitarism is not completely understood; however, available evidence suggests GH as the principal player due to its interaction with many other hormonal and/or peptidic systems (7491). These data are supported by evidence that GHD is the most common pituitary defect in TBI, either isolated or associated with other deficiencies. However, many studies on metabolic impairments in classical hypopituitarism demonstrated that alterations are equally prevalent between isolated GHD or multiple deficits (7991), suggesting GHD as the principal actor. An interaction with untreated hypogonadism cannot be ruled out because T replacement is frequently forgotten or underestimated, whereas hypothyroidism and hypocortisolism have always been treated in patients with hypopituitarism due to their fundamental importance for life. BMI was similar in those with TBI with hypopituitarism and in those without, suggesting that the data were independent of obesity. In summary, TBI patients with hypopituitarism frequently present metabolic alterations, particularly in terms of altered glucose levels, insulin resistance, and hypertriglyceridemia. In view of the risk for premature cardiovascular death in patients with hypopituitarism (7788), major attention should be paid to those who encounter TBI because they suffer from the same comorbidities and may present other deterioration factors due to pharmacological treatments and restriction in participation in life activities and a healthy lifestyle.

Table 6

Clinical and Metabolic Characteristics of TBI Patients With Hypopituitarism and Without Hypopituitarism Evaluated in a Cross-sectional Retrospective Study

Variables Patients Without Hypopituitarism Patients With Hypopituitarism P 
Age, y 37.1 ± 2.5 46.4 ± 3.7 <.02 
Gender (M/F), n 24/15 14/1 <.01 
BMI, kg/m2 24.1 ± 1.1 25.5 ± 1.3 ns 
GCS 9–12, % (n) 11.1 (4) 33.3 (5) ns 
GCS (<9), % (n) 88.9 (35) 66.7 (10)  
Time after injury, y 5.1 ± 1.1 7.4 ± 2.1 ns 
Days of coma 14.0 ± 2.7 1.8 ± 0.8 <.003 
Epilepsy, % (n) 23.7 (9) 6.7 (1) <.03 
Pituitary dysfunction, % (n) // 100.0 (15)  
    Isolated // 40.0 (6)  
    Multiple // 26.6 (4)  
    Total // 33.3 (5)  
Affected axes, % (n)    
    GH // 80.0 (12)  
    ACTH // 46.7 (7)  
    LH/FSH // 60.0 (9)  
    TSH // 46.7 (7)  
    ADH // 20.0 (3)  
    Hypertension, % (n) 5.1 (2) 20.0 (3) ns 
    Altered glucose, % (n) 2.6 (1) 33.3 (5) <.005 
    Dyslipidemia, % (n) 12.8 (6) 46.7 (7) <.01 
Glucose, mg/dL 81.4 ± 1.5 88.7 ± 5.5 ns 
Insulin, μIU/mL 16.6 ± 1.0 22.4 ± 3.6 .069 
HOMA-IR 3.4 ± 0.2 4.8 ± 0.8 <.02 
Total cholesterol, mg/dL 192.7 ± 11.1 204.1 ± 14.5 ns 
HDL-cholesterol, mg/dL 53.1 ± 3.2 48.8 ± 3.2 ns 
LDL-cholesterol, mg/dL 112.5 ± 8.3 118.8 ± 12.1 ns 
Triglycerides, mg/dL 98.0 ± 16.8 161.3 ± 29.3 <.05 

Abbreviations: M, male; F, female; ns, not significant; LDL, low-density lipoprotein; ADH, anti-diuretic hormone; //, no hormonal deficiency. Data are expressed as mean ± SEM or percentage (absolute number). Percentages are calculated separately for each group. [Modified from F. Prodam et al: Metabolic alterations in patients who develop traumatic brain injury (TBI)-induced hypopituitarism. Growth Horm IGF Res. 2013;23:109–113 (81) with permission. © Elsevier.]


Source:
Harvard
Media Contacts: 
Homa Shalchi – Harvard
Image Source:
The image is credited to Harvard.

Original Research: Open access
“Association of Concussion Symptoms With Testosterone Levels and Erectile Dysfunction in Former Professional US-Style Football Players”. Rachel Grashow et al.
JAMA Neurology. doi:10.1001/jamaneurol.2019.2664

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