Experts look for answers to nature of pituitary dysfunction after traumatic brain injury

Traumatic brain injury has received increased attention in recent years primarily due to two highly visible groups affected by the condition. Soldiers returning from Iraq and Afghanistan have exhibited blast-related brain dysfunction in numbers greater than those of earlier conflicts, and professional football players have forced the NFL to recognize the chronic traumatic encephalopathy that follows some concussions.

Traumatic brain injury (TBI) is a significant health concern worldwide, resulting in 2.5 million ED visits, hospitalizations and deaths in the United States in 2010, according to the CDC.

TBI severity, based on the Glasgow Coma Scale, is categorized as mild, moderate or severe. Some of the most common TBI causes are falls, unintentional blunt trauma, motor vehicle accidents, sports-related head trauma and blast exposure. In the most severe cases, these injuries can be devastating, impairing quality of life and causing significant disabilities. Even mild injuries can dramatically affect a patient’s life, including causing pituitary dysfunction in some patients.

Although first reported in the literature in 1918, pituitary dysfunction after TBI garnered little attention from endocrinologists until the past decade or so.

“Endocrinologists are very disconnected from patients with trauma,” Randall J. Urban, MD, professor and chair, division of endocrinology, department of internal medicine at the University of Texas Medical Branch, told Endocrine Today. “They do not in the course of their work flow encounter patients with trauma.”

Urban and colleagues published one of the seminal papers in this area in 2001. “When I was contacted about this, it was something that had never crossed my mind,” Urban said. “Our study published in 2001 and Dan Kelly’s study published in 2000 increased the awareness of this, which led to about a decade of prevalence studies. It is being investigated closer now because of the national interest with chronic traumatic encephalopathy.”

In this issue, experts discuss why it is difficult to conduct research on TBI-induced pituitary dysfunction; symptoms, screening and treatment recommendations; and direction for future research.

Hormone deficiency after TBI

Although the precise pathophysiology is still unknown, the current thinking is that during a TBI a direct mechanical injury or secondary insults — such as hypotension, hypoxia and brain swelling — damage the pituitary gland, leading to hormone deficiencies. Some hormone issues appear immediately, whereas others develop with time. For instance, in the immediate aftermath of a TBI, a patient may develop adrenal insufficiency, diabetes insipidus and hyponatremia. In time, problems such as hypothyroidism, hypogonadism and hyperprolactinemia may arise.

While this is a burgeoning area of research, the current literature is sparse. “The studies that have been done to date are largely either retrospective studies or small prospective studies,” Tamara Wexler, MD, PhD, director of the Pituitary Center at NYU Langone Medical Center, told Endocrine Today.

Obtaining randomized, prospective, placebo-controlled, double blind studies may be challenging in this arena, according to Margaret E. Wierman, MD, professor of medicine, physiology and biophysics and director of the pituitary, adrenal and neuroendocrine tumor program at the University of Colorado Anschutz Medical Campus. “It’s going to be difficult to do them,” she said.

In her own work, Wierman and colleagues had trouble recruiting patients for a study testing testosterone treatment during the acute rehabilitation period. At the time, there was fear about the dangers of testosterone.

“We didn’t get a good, controlled study,” Wierman said. “The other difficulty in a single site is you’re recruiting patients with different severity or Glasgow Coma Scales and the time post-injury. You have all these variables that would have to be controlled. You need a multicenter trial to look at this. As far as I know, no one is doing it.”

Current data at odds

The data obtained to date are discordant in key areas. For instance, the prevalence of post-TBI pituitary dysfunction has been difficult to pin down, with large variations depending on the study.

“Chronic pituitary deficiencies have been reported in 15% to more than 30% of patients after TBI,” Wexler said. “Reports of pituitary deficiency in the acute period after injury are as high as 50% to 75%.”

Urban’s 2001 study, which included 70 adults with TBI, put the incidence of pituitary abnormalities at about 30%. In their 2000 study, Kelly and colleagues found that 40% of patients had some degree of pituitary dysfunction

There are several reasons for the fluctuating prevalence rates. “The lack of a gold standard test for growth hormone deficiency and the confusion over what is a deficiency vs. suboptimal secretion make the prevalence data variable,” Urban said. “What test you do, where you set the cutoff limit will all change the prevalence of an abnormality.”

There are other cofounding factors. “It depends on how the hormonal deficiency is assessed and the time post-injury as well as the severity of the injury as it relates to the TBI,” Wierman said. “In addition, many of the medications that are given during the acute injury or later during the acute rehabilitation or chronic rehabilitation may impact hormone production.”

Concussion categorization is not standardized. “It would help to have a standardized way to describe concussions,” Wexler said. “It is more difficult to interpret outcome measures without defined input criteria.”

In addition, prevalence studies are not that common, Wexler said. “The variance in the populations being studied and in the study design most likely account for the spread in the reported prevalence. Some studies look only at patients who have an overnight stay in the hospital because the brain injury was so severe. Some studies look only at patients who present with a certain type of symptom. These may not be the same population.”

When to initiate screening

There is no consensus on when to test patients with TBI for pituitary dysfunction, according to Endocrine Today Editorial Board member Laurence Katznelson, MD, professor of neurosurgery and medicine and medical director of the pituitary center at the Stanford University Medical Center. “Patients can show evidence of pituitary dysfunction early after the injury, but it may improve,” he said. “Usually, it’s found that although there can be some late comers when pituitary function seems to normalize, somewhere around 6 to 12 months after the event is when we should start the testing because for most patients, if they are pituitary deficient by then, they will remain pituitary deficient.”

The literature suggests that the incidence is high immediately after injury, according to Wierman. “If you look at the old literature ... in the first 2 weeks after the injury, the incidence is way above 50%, maybe 70% to 100% of subhormonal abnormalities,” Wierman said. “Then, it falls by 3 months. By 1 year, most the hormonal abnormalities recover, although in some studies, new hormonal abnormalities occur.” Some of these early studies were complicated by selection bias and inadequate testing criteria.

“The pendulum had almost swung the other way, with a few longitudinal studies showing this recovery by a year saying, ‘Just ignore it all unless it’s acute renal insufficiency because it’s going to recover on its own,’” Wierman said.

Appropriate patients for testing

The literature also is discordant on which patients should be tested for hypopituitarism. Pituitary dysfunction can be difficult to diagnose because the symptoms are subtle and often look like TBI symptoms, such as fatigue, problems with concentration and irritability. “Symptoms of pituitary deficiencies might overlap with other post-concussive symptoms,” Wexler said.

Some experts said they wonder whether all patients should be routinely screened for neuroendocrine deficiencies in the presence of TBI. “There’s some debate whether we should test all patients who have brain injury or just those that have some symptoms, such as fatigue or weight gain, which a lot of these patients already have,” Katznelson said. “We may be testing most of these patients anyway.”

In their review paper, Dubourg and Messerer found that participating in sports, particularly combat sports, increased the risk for hypopituitarism, specifically GH deficiency. They recommended screening athletes who were exposed to chronic repetitive TBI.

Based on the results of a population-based cohort study, Danish researchers reached a different conclusion. Klose and colleagues studied 439 patients and 124 healthy controls who underwent dynamic assessment of GH secretion 2.5 years after TBI. They found that prevalence of post-TBI GH deficiency depended on the diagnostic test used. In the end, their findings call into question the evidence for routine pituitary evaluation in TBI.

When it is time to test a patient with TBI, the endocrinologist should first take a history and perform an exam, looking for evidence of hypopituitarism, such as sexual dysfunction (in men) or weight gain, according to Katznelson.

Screening tests

The patient would then require full testing for neuroendocrine dysfunction, which involves a typical pituitary panel: a thyroid function test, a thyroid-stimulating hormone and free thyroxine test, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), testosterone (in men), prolactin, adrenocorticotropic hormone and cortisol, GH and insulin-like growth factor I.

“In the rare patient where there’s been damage to the posterior pituitary, they would get a water deprivation test to see if they need vasopressin therapy,” Wierman said.

For suspected GH deficiency, patients will undergo a glucagon stimulation test.

These tests must be performed at specific time points, and some tests are more reliable than others. “IGF-I is used as a screening test for growth hormone deficiency, but it’s not an ideal screen,” Wexler said. “The best test is actually a dynamic test in which GH secretion is stimulated, with measurement to ensure that it is appropriately produced.”

It is not necessary to test menstruating women who are not on birth control, according to Wexler, as regular menses are themselves an indication of an intact gonadal axis. Women who do not have regular periods should have their FSH, LH, estradiol and prolactin levels checked.

In men, it is best to check LH, FSH and testosterone, according to Wexler. “The diagnosis of low testosterone in men should be made only on the basis of early morning measurement; guidelines recommend two early morning measurements.”

Common pituitary problem after TBI

Urban has found that the most common problem after TBI has been GH deficiency. These patients had a similar symptom complex. The first was profound fatigue. “A lot of times people would be cutting their job in half or quitting their job,” Urban said. “They could no longer function in that regard.” Second, these patients experienced cognitive issues in three main areas: short-term memory, processing speed and executive function.

However, other than an abnormal response to glucagon stimulation tests, many of these patients appeared to have normal pituitary function, according to Urban. Those results may be due to the inadequate testing currently available.

“There’s a lot of controversy about the testing,” Urban said. “No one has a great test for GH deficiency. The cutoff points are somewhat arbitrary. Less than 3 ng/L is GH deficiency; between 3 ng/L and 10 ng/L is this gray zone; greater than 10 ng/L is normal. Does weight have a factor? Do other illnesses have a factor? All of this uncertainty around the testing.”

After studying the effects of GH replacement in these patients, Urban said his group realized that this was not really a GH deficiency, but abnormal GH secretion. So, they expanded the cutoff points to include people who had a response of 5 ng/L to 8 ng/L, “who, if you were looking for GH deficiency, you would never consider that,” Urban said.

They found that after 2 months of GH therapy, their patients’ fatigue began to decrease. At 4 to 5 months, their cognition began to improve. “Usually, by a year, they’re going to be as good as they’re going to be on this,” Urban said.

Urban and colleagues have been able to demonstrate that physical function, maximal oxygen consumption and fatigue improve with treatment. And some of these improvements have been dramatic, with patients returning to their jobs.

Lifelong hormone replacement

Researchers are still trying to determine whether patients should remain on hormone replacement indefinitely. “I always tell my patients that I don’t know whether they’re going to have to be on this forever,” Urban said. “Perhaps they won’t. My experience so far is that most patients that I have are still on it. Very few have stopped.”

Some patients develop complete pituitary deficiency; they require lifelong hormone replacement at physiologic levels or face long-term cardiovascular, metabolic or fertility complications, according to Wierman. “In the patient who has acquired hypopituitarism, partial or complete, which is going to be rare, they need the same kind of attention and follow-up as any patient with pituitary insufficiency,” she said.

Although it is clear that hormone replacement works — improving cognition, fatigue and quality of life — more research is needed. “What hasn’t been done yet is any kind of intervention studies that show the change in either the rate of outcome or the ultimate recovery from TBI with hormonal therapies,” Wierman said.

Chronic disease state

Based on their research, Urban and colleagues speculate that something larger is going on the brains of some TBI patients.

“Our overall speculation on this is controversial,” Urban said. They believe that in a subset of people, brain trauma — whether it is mild, moderate, severe or even repetitive — kicks off a chronic inflammatory process that leads to pituitary dysfunction.

“It becomes, in some ways, a chronic disease,” Urban said. “They develop a chronic disease like you would think of diabetes as a chronic disease.” This chronic disease inhibits the ability to produce GH. “Then, we replace GH, we find that these symptoms, the fatigue and the cognition, most of the time get better,” he said.

The team also surmises that the chronic traumatic encephalopathy seen in football players may be the end stage of this disease, and “it may manifest itself throughout the population and the people who are susceptible in different ways,” Urban said.

Much of the research to date has made it clear that a moderate or severe TBI can dramatically affect pituitary function. The question remains whether the same can be said about mild, repetitive trauma.

“There aren’t enough data,” Wierman said. “Some of the earlier papers that suggested GH deficiency was common, suggested it happened with mild, multiple head injuries — those were usually associated with a lack of rigorous testing for GH deficiency and spurious therapy with GH for those causes.”

Hunt for biomarkers

Researchers are on the lookout for ways to predict which patients are at risk for pituitary dysfunction. Antibodies may be one avenue for future research.

“There have been studies using antipituitary and antihypothalamic antibodies, for example, and there does appear to be a correlation with the development of these antibodies with subsequent hypopituitarism, although this is still not 100% correlation,” Katznelson said.

Research by Tanriverdi and colleagues found that autoimmunity may play a role in the development of post-TBI pituitary dysfunction. The researchers detected antipituitary antibodies and antihypothalamus antibodies in samples from 61 amateur boxers who were exposed to sports-related TBI.

Research from Taheri and colleagues showed that circulating microRNAs may be potential biomarkers for TBI-induced pituitary dysfunction. The researchers studied microRNA expression in 38 patients in the acute phase of the study; in the chronic stage, they studied 25 patients who sustained a TBI 5 years earlier.

In a retrospective review of 166 adults with TBI, da Silva and colleagues found that certain injuries could be predictors of TBI-induced hypopituitarism. Their results demonstrated that patients who were involved in a motor vehicle accident as well as those with posttraumatic seizures, intracranial hemorrhage or petechial brain hemorrhages were at high risk for hypopituitarism.

Future directions for research

More research is needed to determine the risk for children, especially those who participate in contact sports.

“This has been a big concern with regard to children’s sports, particularly the contact sports, and about how old children should be when they participate because of the concern of not only concussion and long-term brain effects from concussion, but also the impact on pituitary dysfunction. We need to think hard about children’s involvement in contact sports and the impact this may have on their future endocrine health,” Katznelson said.

Soldiers are at great risk for sustaining TBIs, so more study is needed on how to better protect them. Currently, researchers are working on better helmet designs, ear plugs, neck braces and armor, according to Wierman.

Researchers must continue to determine the best way to predict which patients are at greatest risk for TBI-induced hypopituitarism, Wierman said. They must continue to identify the most appropriate therapies and rehabilitation. “[According to] my reading of the literature, we’re not there yet to know that.”

There must be a total shift in thinking, according to Urban. “It’s really starting to think about this differently,” Urban said. “To begin to think about this like we would diabetes and think about it as a chronic disease and try to understand why some people are predisposed to developing this and others aren’t.” – by Colleen Owens

• References:
• CDC. Injury Prevention & Control: Traumatic Brain Injury & Concussion. Available at: www.cdc.gov/traumaticbraininjury/get_the_facts.html. Accessed Aug. 11, 2016.
• da Silva PPB. SAT-0732. Presented at: Endocrine Society’s 96th Annual Meeting and Expo; June 21-24, 2014; Chicago.
• Dubourg J, Messeser M. Neurosurg Focus. 2011;doi:10.3171/2011.8.FOCUS11182.
• Kelly DF, et al. J Neurosurg. 2000;93:743-752.
• Klose M, et al. J Clin Endocrinol Metab. 2014;doi:10.1210/jc.2013-2397.
• Lieberman SA, et al. J Clin Endocrinol Metab. 2001;86:2752-2756.
• Silva PP, et al. J Neurotrauma. 2015;doi:10.1089/neu.2015.3998.
• Taheri S, et al. J Neurotrauma. 2016;doi:10.1089/neu.2015.4281.
• Tanriverdi F, et al. Eur J Endocrinol. 2010;doi:10.1530/EJE-09-1024.

• For more information:
• Laurence Katznelson, MD, can be reached at the Stanford Neuroscience Health Center, 213 Quarry Road, MC5958, Palo Alto, CA 94304; email: katznels@stanford.edu.
• Randall J. Urban, MD, can be reached at the University of Texas Medical Branch, Department of Internal Medicine, 301 University Blvd., Galveston, TX 77555; email: rurban@utmb.edu.
• Tamara Wexler, MD, PhD, can be reached at NYU Diabetes and Endocrine Associates, 530 First Ave., Suite 5E, New York, NY 10016; email: tawexl@gmail.com.
• Margaret E. Wierman, MD, can be reached at the University of Colorado, Endocrinology MS8106, 12801 E. 17th Ave., RC1South, Aurora, CO 80045; email: margaret.wierman@ucdenver.edu.

Disclosure: Katznelson, Urban, Wexler and Wierman report no relevant financial disclosures.

Should screening for TBI-induced pituitary dysfunction include all patients or only those with certain symptoms?

Screening all patients could present a financial burden.

After TBI, justification can be made for endocrine screening on the basis of symptoms. Symptoms that should prompt endocrine screening in TBI survivors include precocious puberty, poor linear growth, pubertal delay, metabolic syndrome, galactorrhea, unexplained fatigue or anorexia/failure to gain weight. However, the limitation of symptom-based screening is that a chronic syndrome after TBI can lead to similar symptoms. Thus, prospective screening should be performed in a targeted manner at least 6 months and 1 year after TBI in certain severities of TBI, according to research from Reifschneider and colleagues (J Clin Med. 2015;doi:10.3390/jcm4081536).

About 25% of survivors of severe TBI have abnormal endocrine screening at 1 year after injury. One meta-analysis suggests that confirmed deficiencies may occur in closer to 20% of TBI survivors (Tanriverdi F, et al. Endocr Rev. 2015;doi:10.1210/er.2014-1065). In another study, Schneider and colleagues found pooled prevalences of hypopituitarism in 16.8% of those whose TBI was mild, 10.9% in those with moderate TBI and 35.3% of those with severe TBI (JAMA. 2007;298:1429-1438). However, most individual studies indicate that risk for endocrine deficiency is unrelated to severity of injury, and instead may be more related to history of skull fracture or hemorrhage. In addition, there are no data published that inform us of the prevalence of endocrine deficiency after concussion.

In their recent meta-analysis, Reifschneider and colleagues recommended performing endocrine screening in all patients who required intensive care hospitalization and in those who had moderate or severe TBI. In prospective evaluation, at least 40% of children still had impaired quality of life at 1 year after moderate to severe head injury. Most commonly affected are young adults (aged 15-24 years), primarily due to motor vehicle accidents, followed by children aged 0 to 4 years experiencing falls, with boys affected more than girls. At least 5.3 million Americans live with disabilities due to sequelae, and more than 17 million TBIs occur annually in the United States.

Thus, screening all TBI survivors would create a significant financial burden. However, about one-fifth of TBIs are classified as severe, according to Reifschneider and colleagues. Thus, screening should be based on indications that include a combination of the survivor’s symptoms and history of injury severity.

Susan R. Rose, MD, is a professor of pediatric endocrinology and metabolism at Cincinnati Children’s Hospital Medical Center at the University of Cincinnati. Disclosure: Rose reports no relevant financial disclosures.

All cases of severe and moderate TBI should be screened.

Hypopituitarism is a common complication following significant TBI, with approximately 25% of long-term survivors of severe or moderate TBI showing some degree of pituitary dysfunction. GH deficiency is the most common problem.

Patients with posttraumatic hypopituitarism have worse quality of life and exercise performance compared with those with similar degree of TBI but intact pituitary function. However, there is a considerable overlap in symptomatology between the two groups. Most patients with significant TBI have ongoing neurocognitive and neuropsychiatric symptoms, and so nonspecific symptoms are of little discriminatory value to be used to select patients for screening, although more specific symptoms, such as amenorrhea in premenopausal women or loss of libido/erectile dysfunction in younger men, are more suggestive of hypopituitarism.

Therefore, I believe that all patients with severe or moderate TBI as assessed by the Glasgow Coma Scale or CT scan appearance should undergo formal structured assessment of pituitary function to identify those with hypopituitarism who may benefit from pituitary replacement therapy to improve quality of life and enhance rehabilitation and recovery following the TBI. Those with mild TBI are at low risk for hypopituitarism, and therefore, testing is indicated in selected cases with more specific symptoms.

Amar Agha, MD, is a consultant endocrinologist at the Beaumont Hospital and the RCSI Medical School in Dublin, Ireland. Disclosure: Agha reports no relevant financial disclosures.