In the name of God

Endocrine dysfunction after traumatic brain injury Hamid. R. Bazrafshan, M.D. Endocrinologist, Neuro Endocrine Fellow, Germany Isfahan, 2017

Introduction Traumatic brain injury (TBI) still remains a serious concern and one of the leading causes of death and disability, particularly among young adults Road traffic accidents are the most common cause of TBI Traumatic brain injury has been recently recognized as a leading cause of pituitary dysfunction

Introduction… 25-50% of the patients have been reported to have some degrees of pituitary dysfunction even after mild TBI. Current data clearly demonstrate that sports-related chronic repetitive head trauma due to amateur boxing and kickboxing might result in pituitary hormone deficiencies, in particular, isolated GH deficiency.

Pathophysiology and mechanism of TBI Hypoxic insult or direct mechanical injury to the hypothalamus, pituitary stalk, or the pituitary gland Compression from hemorrhage, edema, or increased intracranial pressure; and vascular injury to the hypothalamus or the pituitary gland However, none of these mechanisms have been proven, and the mechanism of sports-related head trauma-induced pituitary dysfunction is still unclear ?

Pathophysiology… The traumatic rupture of the pituitary stalk results in anterior lobe infarction because of disruption of the portal blood supply between the hypothalamus and anterior pituitary. Structural abnormalities in the hypothalamus and the pituitary commonly include anterior lobe necrosis, posterior lobe haemorrhage or stalk laceration . Patients with TBI-induced hypopituitarism may benefit both physically and psychologically from appropriate hormone replacement therapy.

Pathophysiology… A possible role of autoimmunity has been suggested by studies conducted in animals Supporting these experimental findings, a significant association between antipituitary antibody (APA) positivity and hypopituitarism 3 years after TBI has been clearly demonstrated in a very recent clinical study

WHAT HORMONE PROBLEMS CAN HAPPEN WITH TBI? Problems that often occur soon after TBI include: Adrenal insufficiency Diabetes insipidus Hyponatremia Problems that may occur later include: Hypothyroidism Hypogonadism Growth hormone deficiency Hyperprolactinemia

The most common endocrine complication after a TBI is syndrome of inappropriate antiduretic hormone (SIADH). SIADH causes a dilutional hyponatremia secondary to inappropriate renal water conservation.

Key discussion points: how to identify the sub-population of patients with TBI-induced hypopituitarism; who should conduct testing and when; and how to raise awareness of the problem among the medical community.

Definition Traumatic brain injury (TBI) is a nondegenerative, noncongenital insult to the brain from an external mechanical force, possibly leading to permanent or temporary impairment of cognitive, physical, and psychosocial functions, with an associated diminished or altered state of consciousness.

Epidemiology Anterior pituitary insufficiency due to pathologic causes was first reported in 1914 by Simmonds. Simmonds described septic pituitary necrosis in a previously healthy woman with severe puerperal sepsis who, before ultimately dying in a coma, experienced menopause, muscle weakness, dizziness, episodic loss of consciousness, anaemia and premature ageing.

Figure 1 Estimates of the global incidence of traumatic brain injury Roozenbeek, B. et al. (2013) Changing patterns in the epidemiology of traumatic brain injury Nat. Rev. Neurol. doi:10.1038/nrneurol.2013.22

Causes include: Falls Motor vehicle accidents Violence, such as gunshot wounds, child abuse, or beatings Injuries from sports or during combat (such as explosions)

TBI Classification: 1.Acute and Chronic Acute phase: generally accepted as the first 10 or 14 days after TBI Chronic phase: defined as at least 3 months after TBI 2.Mild ,Moderate ,Sever TBI

Acute and Chronic Stages of Pituitary Dysfunction After TBI Multiple transient endocrine abnormalities in the initial (~ 𝟑−𝒎𝒐𝒏𝒕𝒉) period following TBI Some problems resolve in the following months Smaller proportion of new dysfunctions emerge during the same period After one year, the pattern of pituitary dysfunction is considered to be relatively stable

Studies

Characteristics of Studies on Pituitary Function After TBI Remarks Severity Dynamic Tests Used Time After Event Design First Author, Year - 86% GCS ≤12 GHRH+ARG 12–64 mo Cross-sectional Bondanelli, 2004 45% GCS ≤ 12, 21% GCS ≤8 3 and 12 mo Prospective Aimaretti, 2004, &2005 100% GCS≤13, 58% GCS≤8 GST, ITT, GHRH+ARG, SST 6–36 mo Agha, 2004 100% GCS≤13 GHRH+GHRP-6 1–22 y Popovic, 2004 100% GCS≤13, 64%GCS≤8 GST 7-20 d,6 mo, &12 mo Agha, 2004, &2005 (continued)

Charachtristic ... Remarks Severity Dynamic Tests Used Time After Event Design First Author,Year Endocrine testing only if clinical suspicion of hypopituitarism in a questionnaire (n=99), dynamic testing only if abnormal basal Values 100% GCS ≤8 GST, ITT, GHRH+GHRP-6 At least 1 y Cross-sectional Leal-Cerro, 2005 Dynamic testing only if pathological results at 3 mo or pathological baseline values at 12 mo 78% GCS≤12, 64%GCS≤8 GHRH+ARG, SST 3&12 mo Prospective Schneider, 2006 (continued)

Charactristic … Severity Dynamic Tests Used Time After Event Design Remarks Severity Dynamic Tests Used Time After Event Design First Author,Year - 40% GCS≤12, 25% GCS≤8 GHRH+GHRP-6 24 h & 12 mo Prospective Tanriverdi, 2006 100% GCS≤8 ITT, GHRH+ARG, SST 5–47 mo Cross-sectional Herrmann, 58% GCS≤12, 38% GCS≤8 ITT, GHRH+ ARG, SST 10–27 mo Klose, 2007 No dynamic test for ACTH 69% ≥ 1-d coma GST 1.2–31 y Bushnik, 2007 Median, GCS=7 GHRH+ARG, 1 mg ACTH 3 and 6–9 Bavisetty, 2008 (continued)

Charachtristic… Severity Dynamic Tests Used Time After Event Design Remarks Severity Dynamic Tests Used Time After Event Design First Author,Year - ICU stay GHRH+ARG, SST Acute phase and >2 y Prospective Kleindienst, 2009 100% GCS ≤12 1mg ACTH 5–12 mo Cross-sectional Srinivasan, 32% GCS ≤ 12 3–30 mo van der Eerden,2010 33% GCS≤8; hospitalization for at least 3 d ITT or GHRH+ ARG and SST or CRH test At least 1 y Kokshoorn, 2011 Tanriverdi, F., et al. (2015). Endocrine Reviews, 36(3):305-342

Summary of selected studies Results Study design Study objective Investigators (Location) status -hypopituitarism in 35% of the patients 4% with total deficit 6% with multiple deficits 25% with isolated deficits -37% with GHD (25% with severe GHD) -peak GH<9.0 mg 𝐿 −1 -no correlation between the GCS score and the occurrence of hypopituitarism or GHD in pts with TBI-induced hypopituitarism - impaired GH secretion not related to severity of TBI Multi-centre Pop: TBI (n=100) To clarify the occurrence of hypopituitarism, with particular attention to GHD, in a population of patients with TBI and sub-arachnoid haemorrhage (SAH) Aimaretti et al. (Italy) completed (Continued)

Study design Study objective Summary of selected studies … Study design Study objective Investigator (Location) status Multi-centre; Treatment groups: 25 pts with thyroid abnormality treated with Pl or 0.1mg per day LT4; re tested after 6 months 25 pts with cortisol abnormality treated with: -Pl or prednisone (5mg each morning 2.5 mg each evening if they had abnormal cosyntropin stimulation test results and retested after 6 months,or -5mg per day if they had low morning cortisol levels with normal cosyntropin stimulation test results and re-tested after 6 months 50 pts with GHD grouped by response to glucagon testing (< 3 mg 𝐿 −1 or 3–10 mg 𝐿 −1 ). All pts randomized to treatment with Pl or up to a max of 0.6 mg per day rhGH sc. Retested after 6months, 1 and 2 years Assessments: muscle strength, body composition by DEXA, single-fibre function and neuropsychological testing. Dose of rhGH adjusted based on age appropriate IGF-I serum concentrations Pts with no measured deficiencies treated with Pl, but no further re-testing To study the effects of hormone replacement on adults with chronic sequellae ≤1 year after TBI Urban et al. (USA) Ongoing (Continued)

Results Study design Study objective Summary of selected studies … Results Study design Study objective Investigator (Location) status Study 1 preliminary results: Of 62 pts with anterior pit. dysfunction: -30.5% have TBI-induced GHD (nine have severe GHD[five severe TBI] and 10 have partial GHD) -16% have gonadotrophin deficiency (four had severe TBI) -19.3% have ACTH deficiency (eight had severe TBI) -1.6% have TSH deficiency -14.5% have elevated PRL levels (seven severe TBI) Of 70 pts with posterior pit. dysfunction: -5.7% have permanent and 14.3% have transient diabetes insipidus -11.4% have SIADH immediately following Injury Study 1: 70 of 100 pts intended were enrolled as of 30 May 2003. Of these 70 pts: - 61% have severe TBI (GCS < 8/15) -39% have moderate TBI (GCS < 9–13) -average time since injury: 166 months - 69 pts had abnormal CT scan -55 had a mass evacuated 2 studies: Study 1: to establish the prevalence of anterior and posterior pit. Dysfunction in survivors of TBI Thompson et al. (Ireland) Ongoing (Continued)

Results Study design Study objective Summary of selected studies… Results Study design Study objective Investigator (Location) status Study 2 preliminary results: Of 44 pts with anterior pit. dysfunction; 38.5% had TBI-induced GHD (two severe&15 partial GHD) - 57% had gonadotrophin deficiency - 11% had ACTH deficiency - 2% had TSH deficiency - 43% had elevated PRL levels Of 50 pts with posterior pit. dysfunction; -24% had diabetes insipidus-14% had SIADH Preliminary conclusions: Pit. dysfunction common in survivors of TBI GHD is not confined to pts with severe TBI Pit. dysfunction occurs in the early TBI period Study 2: 50 pts with moderate-to-severe TBI underwent prospective testing of anterior and posterior pituitary dysfunction immediately, 6 months and 1 year after TBI. Of the 50 pts: 66% had severe TBI (GCS<8) 34% had moderate (GCS 9-13) TBI average time since injury: 11.9±4.4 days 50 pts had abnormal CT scans 41 pts had a mass evacuated Study 2: to establish the natural history of pit. Dysfunction following acute TBI Thompson et al. (Ireland) ongoing (Continued)

Ghigo, E., et al. (2005). Brain Injury, 19:9, 711-724 Summary of selected studies Results Study design Study objective Investigator (Location) status Preliminary results: 28 pts enrolled. some degree of hypopituitarism (excluding secondary amenorrhea) in 68% pts. 10 pts have one affected axis 3 pts have two affected axes GHD in 4/13 (31%) pts hypogonadism in 2/9 (22%) males secondary amenorrhea in all females hypothyroidism in 4/19 (21%) hypocortisolism in 5/19 (26%) hyperprolactinemia in 5/19 (26%) anamnestic diabetes insipidus in 21% To date, no pts have persistent diabetes insipidus Prospective study screening 80 pts following TBI.Assessments include clinical symptoms; cognitive function and QoL (QoL-AGHDA, SF-36); and measurement of sex steroid, gonadotrophin, thyroid hormone, prolactin and IGF-I levels. Assessments are conducted at admission to the clinic and 3 months after TBI. Pts with abnormalities in at least one axis GHRH-arginine test and ACTH test are re-tested 12 months after TBI To evaluate the pit. function of pts with TBI who have no previous history of GH or glucocorticoid treatment and who are admitted to a neurologic rehabilitation Clinic Stalla et al. (Germany) Ghigo, E., et al. (2005). Brain Injury, 19:9, 711-724

Pituitary TBI

The Vital Functions Energy / macronutrient metabolism Temperature Appetite / Weight, Sleep / diurnal rhythm, Mood / well-being, Reproduction / libido, Pain and muscle tone, Visceral sympathetic / parasympathetic balance

Weakness, fatigue, decreased exercise tolerance Increased body fat table II. Primary clinical signs and symptoms of hypopituitarism. Hormonal deficiency Clinical features ACTH, GH, LH, FSH,TSH GH, LH, FSH LH, FSH GH ACTH TSH Weakness, fatigue, decreased exercise tolerance Increased body fat Decreased musle mass Loss of libido, erectile dysfuction Ischemic heart disease Shortened life span Weight loss Weight gain Urban, R. J., Harris, P.,& Masel, B. (2005). Brain Injury, 19:5, 349-358

Table 3. Frequencies of Hypopituitarism in the Chronic Phase After TBI Severity Multiple Deficiencies Hypopituitarism TSH ACTH LH/FSH GH N First Author, Year 86% GCS≤12 6 14 5 7 4 50 Bondanelli, 2004 45% GCS≤12 ,21% GCS≤8 16 8 70 Aimaretti, 2005 100%GCS≤13,58% GCS≤8 29 1 23 12 18 102 Agha,2004 100% GCS≤13 3 10 67 Popovic, 2004 100%GCS≤13,64%GCS≤8 NI 9 48 Agha,2005 (continued)

Table 3. Continued. Severity Hypopituitarism TSH ACTH LH/FSH GH N Multiple Deficiencies Hypopituitarism TSH ACTH LH/FSH GH N First Author, Year 78% GCS≤12, 64% GCS≤8 3 25 2 6 14 7 70 Schneider, 2006 40% GCS≤12, 25% GCS≤8 5 26 10 4 17 52 Tanriverdi, 2006 58% GCS≤12, 38% GCS≤8 18 104 Klose, 2007 69%≥1-d coma NI 58 12 39 23 64 Bushnik, 2007 MedianGCS 7 15 11 Bavisetty, 2008 (continued)

Table 3. Continued. Severity Hypopituitarism TSH ACTH LH/FSH GH N Multiple Deficiencies Hypopituitarism TSH ACTH LH/FSH GH N First Author, Year ICU stay NI 11 9 23 Kleindienst, 2009 100% GCS≤12 5 10 4 18 Srinivasan, 2009 32% GCS≤12 15 1 6 7 107 van der Eerden, 2010 33%GCS≤8; hospitalization for at least 3d 2 3 112 Kokshoorn, 2011 (continued)

Tanriverdi, F., et al. (2015). Endocrine Reviews, 36(3):305-342 Table 3. Continued. Severity Multiple Deficiencies Hypopituitarism TSH ACTH LH/FSH GH N First Author,Year 100% GCS≤8 15 42 10 11 29 6 170 Leal-Cerro, 2005 5 18 2 13 76 Herrmann, 2006 70 315 51 142 123 156 1203 Total TBI,n 6.2% 27.8% 4.2% 11.8% 10% 13.0% 100% Total TBI, % 50 255 39 129 81 144 957 Total TBI all GCS, n 5.6% 28.8% 4.1% 13.5% 8.5% 15.0% 100.0% Total TBI all GCS, % 20 60 12 246 Total TBI GCS ≤8, n 8.1% 24.4% 4.9% 5.3% 17.1% Total TBI GCS ≤8, % Tanriverdi, F., et al. (2015). Endocrine Reviews, 36(3):305-342

Table 1. Workup of Neuroendocrine Dysfunction Testing Concerns Interpretation Suggested Tests Endocrine Axis Reference range will vary by laboratory. Prepubertal levels are Estradiol<20pg/ml and Testosterone<60ng/dl LH FSH Testosterone(male) Estradiol (female) Pituitary-Gonadal (Continued)

Table 1. Continued. Testing Concerns Interpretation Suggested Tests Endocrine Axis Random growth hormone levels are not helpful due to hormone pulsatility IGF-1 levels are not recommended as sole method of screening Growth hormone levels are measured at baseline and after injection with arginine and GHRH. Levels of <4.1 g/L can be used to diagnose deficiency Growth hormone levels are measured at baseline and then after injection with GHRH and GHRP-6. Levels<10 g/L are considered GH deficient. GHRH-arginine stimulation testing GHRH-GHRP-6 stimulation Testing Growth Hormone (Continued)

Testing Concerns Interpretation Suggested Tests Table 1. Continued. Testing Concerns Interpretation Suggested Tests Endocrine Axis A random cortisol level of < 3 mcg/dl is highly suggestive of adrenal insufficiency Serum free cortisol is not widely available at this time Urine free cortisol is used to screen for cortisol excess, but not generally useful for adrenal Insufficiency Cortisol levels are drawn at baseline and then 30 minutes and 60 minutes after injection of IV Cosyntropin. A level of>18 or 20 mcg/dl at any time point makes the diagnosis of adrenal Insufficiency Cosyntropin stimulation with 250mcg or 1mcg of ACTH Serum free cortisol Pituitary-Adrenal (Continued)

Rothman, M. S., et al. (2007). J Neuropsychiatry Clin Neurosci 19:4 Table 1. Continued. Testing Concerns Interpretation Suggested Tests Endocrine Axis Caution in interpreting tests during illness due to “sick euthyroid” Should be done by equilibrium dialysis method for greater accuracy. Reference range will vary by laboratory Free T4 Pituitary-Thyroid Reference range will vary by laboratory Serum prolactin Prolactin Rothman, M. S., et al. (2007). J Neuropsychiatry Clin Neurosci 19:4

Table 3. Impaired Single and Multiple Pituitary Axes Based on the Physician’s Diagnosis and Depending upon Time after TBI or SAH ≥5y n (%) 3-5 y 2-3 y 1-2 y Hormonal insufficiencies 44(52.4%) 16(19.0%) 6 (7.1%) 7 (8.3%) 2 (2.4%) 1 (1.2%) 24 (40%) 18 (30%) 13 (21.7%) 1 (1.7%) 3 (5%) 28 (52.8%) 19 (35.8%) 8 (15.1%) 3 (5.7%) 5 (9.4%) 34 (53.1%) 21 (32.8%) 11 (17.2%) 4 (6.3%) 2 (3.1%) No disturbances Single axis affected Corticotropic Gonadotropic Thyrotropic somatotropic (Continued)

Hormonal insufficiencies Table 3. Continued. ≥5y n (%) 3-5 y 2-3 y 1-2 y Hormonal insufficiencies 24(28.6%) 3(3.6%) 1(1.2%) 4(4.8%) 2(2.4%) 18(30%) 1(1.7%) 3(5.0%) 5(8.3%) 2(3.3%) 6(11.3%) 2(3.8%) 4(7.5%) 9(14.1%) 2(3.1%) 1(1.6%) 3(4.7%) Multiple axes affected Corticotropic+gonadotropic Corticotropic+thyrotropic Corticotropic+somatotropic Gonadotropic+thyrotropic Gonadotropic+somatotropic Thyrotropic+somatotropic (continued)

Krewer, C., et al. (2016). JOURNAL OF NEUROTRAUMA, 33: 1544-1553. Table 3. Continued. ≥5y n (%) 3-5 y 2-3 y 1-2 y Hormonal insufficiencies 1(1.2%) 2(2.4%) 84(100%) 1(1.7%) 60(100%) 53(100%) 1(1.6%) 64(100%) Corticotropic+gonadotropic+thyrotropic Corticotropic+gonadotropic+somatotropic Corticotropic+thyrotropic+somatotropic Gonadotropic+thyrotropic+somatotropic All axes Total Krewer, C., et al. (2016). JOURNAL OF NEUROTRAUMA, 33: 1544-1553.

Cognitive impairment after TBI: what is the contribution of pituitary dysfunction? Cognitive dysfunction can be an enormous problem after TBI.

Common Cognitive/Psychological Issues After TBI 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

GHD and cognition behaviour  Various behaviours, such as cognitive behaviours related to learning and memory, are known to be induced by GH; the hormone might interact with specific receptors located in areas of the CNS that are associated with the functional anatomy of these behaviours.

GHD and Cognition GH is believed to affect excitatory circuits involved in synaptic plasticity, which alters cognitive capacity. GH also has a protective effect on the CNS, as indicated by its beneficial effects in patients with spinal cord injury.

Quality-of-life, mood and executive functioning Ghigo, E., et al. (2005). Brain Injury, 19:9, 711-724

Park, K. D., et al. (2010). Brain Injury, 24:11, 1330-1335

Prasanna, K. L., et al. (2015). Brain Inj, 29(3): 336-342 Figure 1. The percentage of patients with different pituitary hormone deficiencies in the acute phase on day 1 qnd day 7 after traumatic brain injury. Prasanna, K. L., et al. (2015). Brain Inj, 29(3): 336-342

FIG. 1. Long-term anterior pituitary insufficiencies FIG. 1. Long-term anterior pituitary insufficiencies. Impaired pituitary axes with lowered basal hormonal values depending upon time after traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH); in this analysis, patients with single and multiple impaired axes were included. y, years. Krewer, C., et al. (2016). JOURNAL OF NEUROTRAUMA, 33: 1544-1553.

Hormone Severe TBI Moderate TBI level FT3 FT4 TSH Table II. Detailed hormone profile in percentage in relation to severity, pressure effect and Glasgow Outcome Scale. Severe TBI Moderate TBI level Hormone D-7 D-1 72.72 22.72 4.57 66.66 29.16 4.1 88.46 7.69 3.84 84.61 11.53 Normal Low High FT3 50 87.5 8.33 4.16 72 20 8 76.92 15.38 FT4 68.18 30.81 91.66 92 92.3 TSH (Continued)

level Hormone Severe TBI Moderate TBI Normal Low High GH Cortisol Table II. Continued. Severe TBI Moderate TBI level Hormone D-7 D-1 36.36 59.09 4.54 58.33 33.33 8.33 64 36 61.53 23.07 15.38 Normal Low High GH 81.81 22.72 54.16 45.83 80 20 65.38 3.8 30.16 Cortisol 86.36 9.09 4.5 12.5 100 88.46 11.53 Prolactin (Continued)

Without pressure effect Table II. Continued. Good GOS Poor GOS Without pressure effect With pressure effect level Hormone D-7 D-1 61.76 38.23 26.47 11.76 23.07 69.23 7.69 56.25 31.25 12.5 52.94 47.05 82.35 17.64 50 60.06 33.33 6.06 Normal Low High GH 76.47 23.52 70.58 2.94 26.41 76.92 7.6 15.38 37.5 62.25 5.88 76.66 23.33 54.54 45.45 Cortisol 100 97.05 68.75 18.75 88.23 11.75 96.66 3.33 81.81 9.09 Prolactine Prasanna, K. L., et al. (2015). Brain Inj, 29(3): 336-342

Acute head trauma Chronic TBI Sports-related TBI multiple traumas (recurrent concussion) or repetitive traumas

Hypopituitarism due to Sports-Related Chronic Repetitive Head Trauma Sport TBI Definition of sports-related traumatic brain injury Sports-related TBI is a common public health problem worldwide that is associated with increased morbidity and may cause mortality 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 Concussion is a well-known and most typical injury associated with sports Hypopituitarism due to Sports-Related Chronic Repetitive Head Trauma

Pituitary dysfunction due to sports-related brain injury Neuroendocrine dysfunction has not been routinely investigated until recently. Head is one of the most frequently injured organs among amateur and professional kickboxers. Recently, investigators have evaluated the risk of TBI in football players.

Deficient pituitary hormones Number of bouts Retirement age (years) Table 1. Baseline characteristics of boxers with hypopituitarism and individual antihypothalamus antibodies (AHA) and antipituitary antibodies (APA) titers APA titer AHA titer Deficient pituitary hormones Number of bouts Retirement age (years) Boxing duration (years) Boxing status Age (years) No. Absent 1.16 ACTH 1080 - 7 Active boxer 20 1 1.64 ACTH,GH 330 3 19 2 1000 10 21 28 Retired boxer 44 4 1.32 ACTH, GH 2240 14 47 5 (Continued)

Deficient pituitary hormones Number of bouts Retirement age (years) Table 1. Continued. APA titer AHA titer Deficient pituitary hormones Number of bouts Retirement age (years) Boxing duration (years) Boxing status Age (years) No. Absent 1.64 GH 2400 30 12 Retired boxer 44 6 960 27 49 7 1.32 1100 26 11 50 8 1800 25 9 40 800 37 10 860 28 42

Table 2. Comparison of pituitary dysfunction development between AHA-positive and AHA-negative boxers and between APA positive and APA-negative boxers. AHA-negative boxers (n=48) AHA-positive boxers (n=13) Pituitary dysfunction (PD) AHA-positive and AHA-negative boxers 5 (10.4%) 6 (46.2%)* With PD 43 (89.6%) 7 (53.8%) Without PD APA-positive and APA-negative boxers 8 (17.0%) 3 (21.4%) 39 (83%) 11 (78.6%) χ2=0.14 and P=0.707; Data are given as a number and as a percentage of each category. * χ2=8.84 and P=0.003.

Screening and Testing

The first step in diagnosing hypopituitarism is recording of a detailed patient and family history. In cases of idiopathic hypopituitarism, in particular, the family as well as the patient should be questioned rigorously about any history of head injury because the patient’s memory of the event may be compromised.

Tanriverdi, F., et al. (2015). Endocrine Reviews, 36(3):305-342 chronic repetitivTBI Different clinical scenarios for acute and/or chronic pituitary dysfunction Tanriverdi, F., et al. (2015). Endocrine Reviews, 36(3):305-342

Predictors of Long-term Pituitary Dysfunction After TBI Severity of head trauma Radiological changes Acute pituitary hormone changes (ACTH deficiency and/or central DI) Older age Length of stay in ICU and duration of coma Increased ICP Presence of APAs and AHAs

Suggested Inclusion and Exclusion Criteria for Screening of Hypopituitarism in Patients With Mild, Moderate, and Severe TBI Inclusion criteria 1. Those patients (regardless of the severity of TBI) who need hospitalization for at least 24 hours and who need ICU monitoring, in particular, should be screened during the acute phase and prospectively. 2. Those with a history of complicated mild TBI, moderate TBI, and severe TBI at any time after the event (especially those who have suspicious signs and symptoms of hypopituitarism). (Continued)

Tanriverdi, F., et al. (2015). Endocrine Reviews, 36(3):305-342 Exclusion criteria (these patients could not be screened until more studies are performed) 1. TBI patients in a vegetative state and severely disabled or with low life expectancy 2. Mild TBI patients who are discharged from emergency units and/or who have no loss of consciousness and/or posttraumatic amnesia of less than 30 minutes. Tanriverdi, F., et al. (2015). Endocrine Reviews, 36(3):305-342

Ghigo, E., et al. (2005). Brain Injury, 19:9, 711-724 Routine basal hormonal screening tests for TBI-induced hypopituitarism. Test time Basal hormone test 0900 hours 24 hours Serum cortisol (morning) fT3, fT4, thyroid stimulating hormone (TSH) IGF- ɪ FSH, LH, Testosterone (in men) or 17 bE2 (in women) Prolactin (PRL) Urinary free cortisol (UFC) Patients with polyuria: Diuresis, urine density, 𝑁𝑎 ++ and plasma osmolality Ghigo, E., et al. (2005). Brain Injury, 19:9, 711-724

Dynamic tests Stimulation tests should be performed in patients with suspicion of GHD or hypocortisolism. It is important to highlight that clinical signs of neuroendocrine dysfuction in combination with a history of brain injury should lead to hormonal assessment of the hypothalamo-pituitary axes, even many years after brain injury.

Patients with moderate or severe TBI Assess ACTH deficiency by measuring morning basal cortisol levels in the acute phase ( ≤ 11 mg/dl (300 nmol/L) is diagnostic) Assess ACTH deficiency before discharge when the patient is stable Treat ACTH deficiency Reassess at 6 months Treat ACTH, TSH AND FSH/LH deficiencies as appropriate Reassess at 12 month No hormone deficiencies One or more hormone deficiencies No need to further screening Routine clinical and hormonal follow-up as the other causes of hypopituitarism Tanriverdi, F., et al. (2015). Endocrine Reviews, 36(3):305-342

Ghigo, E., et al. (2005). Brain Injury, 19:9, 711-724

Diagnosis Imaging TBI Damage caused by open head injuries can be seen using brain imaging techniques CT and MRI scans of concussions may appear normal Diffuse tensor imaging (DTI) provide a method for identifying damage to the connections in TBI

The Criteria for Diagnosis Hypothalamic Dysfunction diagnosed when 4 or more systems involved. Hypogonadism is clinical syndrome with low testosterone. It could be primary or central.

HPA axis Diagnostic (Hormonal) Criteria Test Morning (8–9 AM) cortisol Diagnosis of Anterior Pituitary Dysfunction in Adult TBI Patients Tanriverdi, F., et al. (2015). Endocrine Reviews, Diagnostic (Hormonal) Criteria Test < 83–100 nmol/L (or <3 mg/dL): hypocortisolism diagnosed > 500 nmol/L (or >18 mg/dL): hypocortisolism excluded Below upper reference range: secondary adrenal insufficiency Peak cortisol >500 nmol/L (presence of symptoms of hypoglycemia): normal integrity of the HPA axis HPA axis Morning (8–9 AM) cortisol Morning (8–9 AM) ACTH ITT (Continued)

Diagnostic (Hormonal) Criteria Test Cortisol >500 nmol/L: normal integrity of the HPA axis Limited value for the diagnosis of ACTH deficiency Peak cortisol >500 nmol/L: normal integrity of the HPA axis HPA axis . 250 (or 1) mg ACTH test CRH test (100 mg as a bolus iv) GST (1 mg im) Low (<11 pmol/L) Low or normal TRH-TSH-thyroid axis Free T4 TSH Tanriverdi, F., et al. (2015). Endocrine Reviews, (Continued)

Tanriverdi, F., et al. (2015). Endocrine Reviews, 36(3):305-342 Diagnostic (Hormonal) Criteria Test Below or in the normal age-related reference range Adults: GH ≤ 3 mg/L BMI related: if <25 kg/m2, ≤11.5 mg/L; if ≥25– <30 kg/m2, ≤8.0 mg/L; if ≥30 kg/m2, ≤4.2 mg/L, respectively Lean: GH≤10 mg/L, if BMI >35 kg/m2: ≤5.0 mg/L GH ≤3 mg/L Somatotropic (GH-IGF-1) function IGF-1 ITT GHRH+ARG test GHRH+GHRP-6 test GST Tanriverdi, F., et al. (2015). Endocrine Reviews, 36(3):305-342

Therapeutic Approaches

Acute phase Treatment of TSH, FSH/LH, and GH deficiencies Treatment of ACTH deficiency

Chronic phase Treatment of TSH, FSH/LH, and ACTH deficiencies Treatment of GHD GHD, isolated GHD in particular, is one of the most common pituitary hormone deficits due to TBI and sports-related head trauma.

Procedure Principle specific hormone deficiencies Principles of anterior pituitary hormone replacement therapy for patients with TBI. Procedure Principle Know the clinical features of and diagnostic tests for anterior pituitary hormone deficiency Check for signs and symptoms (e.g. weakness, fatigue, increased body fat, decreased muscle mass, loss of libido) Conduct testing of basal TSH, fT4, IGF-I, 0900 Cortisol, LH, FSH, testosterone or oestradiol. Refer to an endocrinologist if results are abnormal. Follow-up in conjunction with an endocrinologist. Monitor signs and symptoms for maximal improvement in cognitive functioning and quality of life Increase awareness of the risk of hypopituitarism in patients with TBI Screen ‘at risk’ patients with TBI for specific hormone deficiencies Determine if there are specific deficiencies As appropriate, identify dosage for replacement therapy Urban, R. J., Harris, P.,& Masel, B. (2005). Brain Injury, 19:5, 349-358

Immediate Hormone Replacement Therapy: Individuals < 1 Year Post-injury Who Require Immediate HRT Legend Yes…..…..................….…oval As Appropriate…..diamond Case by Case.…….pentagon Panhypopituitarism Diabetes Insipidus 2◦ Adrenal Insufficiency 2◦ Hypothyroidism 2◦ Hypogonadism Growth Hormone Deficit (Continued)

Immediate Hormone Replacement Therapy: Individuals < 1 Year Post-injury Who Require Immediate HRT Diabetes Insipidus Urban, R. J., Harris, P.,& Masel, B. (2005). Brain Injury, 19:5, 349-358

Prevention The technology for prevention of TBI is helpful especially in children.

Education is the Key Experts agree that the best ways to prevent concussion are: Play by the rules. Teaching young athletes to respect the rules of their sport is part of good coaching.

Wear the appropriate equipment for your sport and wear it properly Wear the appropriate equipment for your sport and wear it properly. Always close a chin strap if your sport requires a helmet; many concussions occur during practice. Examine the playing field for uneven areas or holes.

Make sure that end posts are padded sufficiently. Practice good sportsmanship. Teaching good sportsmanship is part of good coaching and good parenting minimizing unnecessary aggression on the field. Learn and use proper technique for your sport. Some sports organizations have taken additional action to minimize the risk of concussion by limiting the number of contact practices allowed during the season.

Conclusion Anterior pituitary secretion dysfunction can occur in more than 30% of moderate-to-severe chronic TBI patients. TBI patients with anterior pituitary gland secretion dysfunction have a greater chance of obesity and less functional gain compared to those with normal hormonal function. TBI patients need close observation of anterior pituitary function.

Conclusion… Patients who are still in need of medical treatment even years after TBI or SAH are at risk for neuroendocrine disturbances. All pituitary axes should be assessed, with special regard to gonadotropic and somatotropic axes, which were the most frequently disturbed.

Conclusion … The epidemiology of TBI has changed over time. A shift towards older age of patients with TBI has been observed, especially in high-income countries, with falls representing the primary cause of TBI among the elderly, resulting in more contusional injuries. The high incidence of comorbidities and the frequent use of platelet aggregation inhibitors and oral anticoagulants among older patients have a negative influence on outcome following TBI.

Conclusion … The burden caused by TBI to patients, relatives, caregivers and societies remains high, but reliable quantification is difficult. We recognize a great need for the development of high-quality epidemiological monitoring databases for reliable estimation of incidence, prevalence and outcome parameters. Long-term follow-up of large cohorts could provide definitive information about the cognitive consequences of acute TBI.

Conclusion … Because of the high prevalence rates of Hypopituitarism , it is recommended that a neuroendocrine assessment should be performed ‘‘even in patients who had had trauma many years before;’’ however, little is known about long-term anterior pituitary insufficiency after TBI.

Conclusion … For 40 years researchers have been looking at what they can do to help people with TBI, each and every one of these studies was futile because nothing they came up with helped. Even now, few people are aware of the existence of post TBI hormonal deficiency syndrome It is up to us to educate our fellow physicians about post TBI hormonal deficiency syndrome and how to treat it.

Hormonal replacement for patients with proved isolated gonadal deficit or severe GHD could be reconsidered after re- testing and in the appropriate clinical context. GH is the most common hormone lost after TBI, followed by ACTH, gonadotropins (FSH and LH), and TSH. The underlying mechanisms responsible for pituitary dysfunction after TBI are not entirely clear Recent studies have shown that genetic predisposition and autoimmunity may have a role. Hypopituitarism after TBI may have a negative impact on the pace or degree of functional recovery and cognition.

Take Home Message TBI is associated with sequelae of endocrine dysfunction that can last up to at least a year. Regular surveillance at 6 monthly intervals may be important to detect and manage such sequelae following pediatric TBI.

Take Home message Further exploration of this possibility requires: active collaboration between divisions of endocrinology and rehabilitation at the local level to perform a screening of pituitary function in patients after TBI Creation of a consultancy service by endocrine societies for use by rehabilitation centres Development of continuing medical education (CME) programmes that can be offered as crossover training to the physicians who manage the care of patients with TBIs.

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