Mild traumatic brain injury (mTBI) caused by blast effects of explosive devices is the """"""""signature injury"""""""" of the current Iraq and Afghanistan conflicts, affecting an estimated 18% of deployed American service members. Although termed """"""""mild"""""""" in comparison to brain injuries resulting in death, coma, or paralysis, mTBI, particularly repetitive mTBI characteristic of soldiers deployed to Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF), in Afghanistan, may have devastating personal, professional and domestic consequences. Impairment of memory and concentration, increased anxiety, irritability and mood instability, and sleep disturbance interfere with job and family relationships, producing substantial disability. In cases of civilian TBI from all causes, screening for hypopituitarism has been increasingly recognized as a necessary component in the investigation of the long-term outcome of TBI. Hypopituitarism, as defined by deficient production of one or more pituitary hormones measured at least one year after injury, has been reported to occur in 30-70% of TBI cases, and its occurrence is not related to trauma severity. Hypopituitarism is associated with numerous non-specific symptoms easily mistaken for behavioral symptoms of posttraumatic stress disorder (PTSD) and chronic postconcussive syndrome, including fatigue, anxiety, depression, irritability, insomnia, and decreased quality of life (QoL), as well as changes in body composition including increased fat percentage, hyperlipidemia, and a decrease in muscle mass. If accurately diagnosed as a consequence of hypopituitarism, these symptoms can in most cases be successfully relieved with hormone replacement. Measurement of baseline concentrations of pituitary hormones and their target hormones has been shown to have considerable diagnostic utility in identifying most types of pituitary deficiencies. However, definitive diagnosis of growth hormone deficiency (GHD) and secondary adrenal insufficiency (sAI) typically requires the use of provocative testing. Provocative testing is costly, time-consuming, and laborintensive. In addition, the insulin tolerance test (ITT), which is generally considered the gold standard test for both GHD and sAI, requires intensive medical supervision and is contraindicated in cases of head injury, so it cannot be employed to diagnose GHD or sAI in OIF/OEF Veterans with mTBI. The rationale for this study is based on the high risk for hypopituitarism associated with TBI in civilian settings, the apparent absence of any systematic investigation of pituitary dysfunction after blast mTBI in OIF/OEF service members or Veterans, and the absence of routine screening for hypopituitarism in this population. We propose to investigate the frequency and specific nature of blast mTBI-related hypopituitarism in OIF/OEF Veterans and to devise a reliable, cost-effective, and efficient screening procedure that will direct appropriate therapeutic intervention, facilitate recovery and rehabilitation, and improve QoL. The objectives of the study are: 1) to determine whether pituitary hormone defects that are readily identifiable from the results of basal hormone measurements are more prevalent in OIF/OEF Veterans with blast mTBI than in deployment control subjects not exposed to blast trauma;2) to determine whether the glucagon stimulation test (GST) can substitute for the (contraindicated) ITT as a provocative test for diagnosing GHD and/or sAI in OIF/OEF Veterans with blast exposure mTBI;3) to determine whether evidence of hypopituitarism is associated with increased frequency of sleep problems, symptoms of chronic postconcussive syndrome, depression, and PTSD, lower cognitive performance, adverse changes in body composition, and poorer QoL;and 4) to determine whether a combination of basal hormone measures, serum lipid profiles, body composition indices, and additional demographic, behavioral, and symptom values can be used to diagnose GHD and sAI with acceptable accuracy compared to more expensive and time-consuming provocative testing procedures.

Public Health Relevance

Pituitary gland dysfunction has both negative short- and long- term consequences. Growth hormone deficiency and other pituitary hormone abnormalities that occur with high frequency as a result of civilian mild traumatic brain injury (mTBI) are associated with fatigue, insomnia, depression, decreased muscle volume and strength, decreased sex drive, social isolation, and impairments of learning and memory. In the long term, pituitary hormone abnormalities are associated with high total and LDL (bad) cholesterol, high blood pressure, obesity, increased inflammation, and premature death from cardiovascular disease. These conditions are treatable with appropriate hormone replacement. Determination of the frequency of pituitary abnormalities in OIF/OEF Veterans with blast concussion mTBI and development of criteria to identify Veterans with pituitary dysfunction will enable appropriate clinical testing and treatment to prevent negative short- and long-Summary of comments

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Brain Injury: TBI &Stroke (RRD1)
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VA Puget Sound Healthcare System
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