9.4 Physiological Disorders

As mentioned earlier, traumatic or acquired brain injury can result in significant hormonal abnormalities which in turn can have a negative impact on physiological functioning. Consequences are generally a result of anterior and posterior pituitary dysfunction. The consequences of pituitary dysfunction are shown below.

Table 9.8 Hormone Delivery and the Effects of Insufficiency (p.326 3)



Anterior pituitary







~50% of cells growth hormone (GH)


~10%-25 % of

cells prolactin (PRL)

~10%-15% of cells lutenizing hormone (LH) and follicle stimulating hormone (FSH)



~3%-5% of cells thyroid stimulating hormone (TSH)


of cells  adrenocorticotrophic hormone (ACTH)




Mammary gland

Gonads and Ovaries

Thyroid gland

Adrenal gland

Symptoms of Insufficiency

­  abdominal fat




¯  muscle





­  lactation

secretion of estrogen and progesterone



­  facial wrinkles





¯  libido


pubic hair &

axillary hair

­     dry skin,



 fatigue &

cognitive     deficits


↓cold tolerance & heart rate

­     depression,





vomiting, & under stress,




↓ weight, strength & skin color

Posterior Pituitary




  Mammary gland and Uterus

   Kidney and Arterioles

Symptoms of Insufficiency

­        lactation & uterine contractions

­        blood pressure & water retention


9.4.1 Posterior Pituitary Dysfunction Antidiuretic Hormone Dysfunction (ADH)

What are the more common medical consequences of an acute TBI?
  1. Early studies investigating the impact of an ABI on the posterior pituitary gland have demonstrated a disruption in sodium and fluid balance.
  2. The more common medical consequences of an acute TBI are disorders of salt and water balance resulting in inappropriate secretions of antidiuretic hormone (SIADH), hyponatremia and diabetes insipidus (DI).
  3. Abnormalities of antidiuretic hormone represent one of the most common endocrine disturbances that occur in patients following a TBI 10 Syndrome of Inappropriate Secretion of ADH (SIADH)

Following an ABI who is most likely to develop symptoms of SIADH?

1.    Those who have sustained a severe ABI were more likely to develop symptoms of SIADH. Researchers suggest restricting fluid intake to assist in the resolution of symptoms.

SIADH has been diagnosed in patients when sodium serum levels drop below 135mEg/L (hyponatremia) 30coupled with an inappropriate elevation of urine osmolality 25. Given that adrenal insufficiency can be life-threatening, it should be evaluated when suspected in the acute phase 8. It is generally accepted that adrenal, thyroid and gonadal function should be systematically studied 3-6 months after onset. Reassessment at 12 months should only be done for those patients who had abnormal results at 3-6 months. Assessment for growth hormone deficiency should not be performed until other hormonal deficiencies have been managed 8. It has been suggested that the use of medications such as carbamazepine, SSRI, diuretics, vasopressin analogs, and chlorpromazine may lead to SIADH 30-32.

In a review of 1808 ABI patients conducted by Doczi et al.33, the authors reported 84 patients developed SIADH, with the majority of these patients suffering a moderate (n=60) to severe (n=19) head injury. Of the 84 patients, 43 were found to have developed severe SIADH. Patients’ were diagnosed with elevated intracranial pressure resulting from suspected brain edema, and each required strict fluid restriction. In this group of patients, serum sodium levels were found to be below 125 mmol/litre and each had an osmolality below 270 mosm/kg.  Deterioration of the original injury and the development of complications can result in a delay in the diagnosis of SIADH.

In another study, conducted by Born et al. 34, of the 36 patients who were diagnosed with a severe ABI, all developed signs of SIADH. Six were diagnosed within 4 days of injury (early syndrome), while in the remaining patients SIADH became noticeable 7 or more days (late syndrome) post injury.  The authors also noted that 33% of patients who underwent surgery showed signs of SIADH.  Authors suggested limiting fluid intake (250 to 500 ml per 24 hours) to resolve symptoms. Hyponatremia

What are the symptoms of hyponatremia post ABI and its recommended treatment?

1.    Symptoms of hyponatremia include lethargy, coma, or seizures.

2.    Recommendations for the treatment of hyponatremia, resulting from SIADH, include limiting daily fluid intake.

3.    Administering saline or oral salt appears to be an effective treatment for hyponatremia post ABI.

4.    The death rate for those diagnosed with hyponatremia is 60% higher than for patients who do not have it.

Hyponatremia, defined as serum sodium concentration less than 136 mmol/L 35may result from SIADH or cerebral salt wasting.Prevalence rates for severe hyponatremia among the ABI population have been found to range from 2.3% to 36.6% 36.

Zhang et al. 37, looked at the development of central hyponatremia in a group of ABI patients (n=68; GCS scores were 3-15) and a group of non-ABI patients (n=24).  Blood osmotic pressure was only found to be significantly different between those with a mild or moderate ABI compared to those with a severe TBI. Test results showed urine osmotic pressure was significantly different (p<0.01) between the ABI group and the non-ABI group. No significant differences were noted within the 3 ABI groups. Blood sodium levels between the ABI group and the non-ABI group were found to be significantly different with the ABI group having lower sodium (Na+) concentrations in their blood than the non-ABI group (p<0.02). Within the ABI group, the majority of patients (n=25) who had sustained a severe TBI were diagnosed with hyponatremia and were found to have a significantly lower Na+ than those in the mild to moderate ABI groups (p<0.05) 37.

Moro et al. 38conducted a review of 298 patient files and found 50 patients presented with signs of hyponatremia. Those diagnosed with hyponatremia were found to have worse outcomes, longer stays in hospital and most were diagnosed within the first 3 days of injury. Treatment included sodium supplementation therapy, which was effective for 37 patients. The remaining 13 patients received sodium supplementation therapy and sodium retention therapy with hydrocortisone.  The administration of the hydrocortisone allowed the serum sodium levels to reach the normal range within 3 days as sodium excretion was reduced as was urine volume.

Zafonte and Mann 39and Chang et al. 36each published case studies where hyponatremia was present. Zafonte and Mann 40noted that the patient’s sodium level had decreased to 120mEg/dL, she had lost weight and was clinically dehydrated. The patient was treated intravenously with normal saline and oral salt supplementation. An improvement was found in the patient’s serum sodium levels within days.

Chang et al. 36, in a case study reported on a patient who experienced a rapid drop in his serum sodium levels. This coupled with the results of his other blood tests indicated the presence of hyponatremia. Treatment for this patient included the administration of hypertonic saline and fluid restriction. Over time and after 3 more episodes of hyponatremia, sodium levels increased and stabilized.  Diabetes Insipidus(DI)

Following a severe head injury, what has diabetes insipidus been linked to?

1.    Results of several studies indicate that DI has been linked to lower GCS, lower GOS and a higher mortality rate.

Diabetes insipidus (DI) has been found to occur in patients with mild to severe TBIs and may last anywhere from a few days to a month post injury 41. Simply put, DI results “in the production of large amounts of diluted urine”.  Post traumatic DI may result from swelling around the hypothalamus or posterior pituitary but as the swelling begins to resolve itself so does the DI 42. Individuals suffering from DI may experience severe thirst, polyuria and polydipsia 25.

Hadjizacharia et al. 43,in a study of 436 head injured patients, found 15.4% (n=67) developed diabetes insipidus.Onset of diabetes insipidus for most patients occurred within the first few days of admission to acute care (mean =1.2 days), with treatment beginning on average of 1.6 days post diagnosis. There was a significantly higher incidence of complications in the DI group when compared to the remaining group (p=0.016). Those at greatest risk for developing DI were those whose GCS was </=8. Those in the DI group were also found to have a higher mortality rate.

Agha et al. 44found 13 out of 50 ABI patients developed DI within the first 11 days post injury. It was also noted that these patients had a lower GCS score than those who did not develop DI.  Diabetes insipidus was treated with desmopressin, subcutaneously at first and then orally. Six months post injury only 4 of the 13 patients were found to have persistent DI.  At the 12 month, 3 patients were still being treated for DI.  When accessing patient outcomes, using the GOS, 5 of the 13 with DI had Glasgow Outcome scores between 1 and 3.

What evidence is there supporting the administration of IGF-I post ABI to improve clinical outcomes in those patients who have diagnosed with DI?

1.    There is Level 2 evidence suggesting IGF-I given post ABI may improve clinical outcomes in patients diagnosed with DI.

In an RCT, Hatton et al. 45randomized patients with GCS 5-7 initially to placebo or to  the treatment group that received  insulin-like growth factor-I (IGH-I)  administered as 5 mg rhIGF-I/1ml citrate/NaCL, pH6 via  a continuous intravenous infusion within the first 72 hours that continued for 14 days. Both the control and treatment group were provided with nutritional support. In total 5 patients died during the study: 2 were in the treatment group and 3 were in the control group. Study results indicate those in the treatment group gained weight even though they had a lower caloric intake and higher energy expenditure. The control group lost weight and were found to have greater nitrogen outputs and daily glucose concentrations. Nitrogen intake during week 2 was significantly less in the treatment group (p=0.002) when compared to the control group. Nitrogen output was greater in the control group over the two week study period, compared to the treatment group. Glucose concentrations were also higher in the control group, when compared to the treatment group during the study period. GOS improved, from poor to good, for 8 of the remaining 11 patients in the treatment group. In the control group, the Glasgow Outcome Scale improved in only 3 patients.

9.4.2  Anterior Pituitary Dysfunction

Following a TBI what does the research say about who is at greater risk for developing a hormonal deficiency?

1.    Those who suffer from moderate to severe TBIs are at greater risk for developing hormonal deficiencies.

2.    This may lead to a poorer outcome following a TBI as hypopituitarism has been shown to negatively influence recovery.

Early research indicated that damage to the anterior pituitary dysfunction (APD) was likely to not be reported post ABI 17; however, APD is now increasingly recognized 18. Damage to the APD may lead to a compromise in growth hormone (GH), thyroid, glucocorticoid, sex hormone (testosterone in men/estrogen in women), and prolactin production 18. Clinical presentation of APD varies widely, depending on the particular neuroendocrine axes affected, and the severity and rapidity of damage to that axis. The clinical presentation can range from subclinical disease to marked muscle or cardiovascular collapse 18.

Bondanelli et al. 22noted that anterior hypopituitarism occurred in 26% of the TBI patients in their study. All were approximately, 6 months to one-year post injury. These results compared well to previous studies which noted anterior hypoituitarism occurred in about one-third of those who were 5 years post injury 21;46. Results also indicated that the LH-FSH and GH axes were directly related to the high occurrence of isolated deficiencies 22. Furthermore, complete hypopituitarism was detected in only 1.4% of the 72 participants in the study. Study authors also found that pituitary dysfunction did not appear to be related to the GCS which was noted in several previous studies.

In a systematic review, Urban et al. 47concluded that regardless of the severity of injury, APH deficiencies (including GH deficiency) in those who had had a TBI were more common than originally thought. Difficulties in diagnosis arise because these hormonal deficiencies can produce physical and psychological symptoms which mimic symptoms generally associated with other brain trauma pathology. Urban et al. 47noted that the consequences of these hormonal abnormalities can be significant; for instance, hypopituitarism can increase the risk of ischemic heart disease and even a shortened life span.

Schneider et al. 28;48, found that 56% of the 78 TBI patients who participated, had a least one pituitary axis impairment. Overall, no significant differences were noted when looking at GCS, modified Rankin scores, BMI, and age between those with and without hypopituitarism.  Those with impaired GH secretion were found to be older and had higher BMIs, and lower IGF-I levels. Twelve months post injury fewer patients were affected, but several new cases were diagnosed.

Tanriverdi et al. 49;50in a study of 53 individuals diagnosed with a TBI, measured hormonal levels during the acute stage of recovery and one year post recovery.  During the acute stage of recovery, several patients were found to have at least one hormonal deficiency (hyperprolactinemia (n=6) and low T3 syndrome (n=27)). A comparison of mean hormone levels from the acute phase to the post recovery period of 12 months revealed no significant differences inthe following levels: fT4, PRL, LH, free testosterone and ACTH. When looking at total testosterone levels, TSH, fT3, FSH and IGF-I increased significantly (p<0.05), while GH levels and cortisol levels decreased over the 12 month period 50.Tests completed at 3 years post injury, revealed 7 of the original 13 diagnosed as GH deficient were fully recovered, with one patient being newly diagnosed. Of those diagnosed as ACTH deficient, 5 of the 6 had recovered and one more patient was newly diagnosed 49. Tanriverdi et al. 49found that GH deficiency, the most common deficiency post ABI, improved over time in those with mild or moderate ABIs, but those with severe ABIs had persisting symptoms.  Another study conducted by Tanriverdi et al. 51, found that basal hormone levels (cortisol, prolactin and total testosterone (males only)) were related to severity of injury.

Agha et al. 52in one of the largest studies of individuals (n=102) with a moderate to severe TBI found a high prevalence of undiagnosed hypopituitarism.  More than a quarter of study subjects were found to have a large amount of undiagnosed anterior hormone deficiency. Those who were GH-deficient had a significantly higher body mass index (p=0.003) and lower IGF-I concentrations (p<0.001) than GH-sufficient patients. No relationship was found between the GCS, age and other pituitary hormone abnormalities and deficiencies of the GH or ACTH (p > 0.05) 52.

Cernak et al. 53found changes in hormonal levels were affected by the level of injury a patient had sustained. Those with severe injuries were diagnosed with greater hormonal changes. In patients with a mild TBI TSH levels were elevated for the first 3 days following an injury; however, in patients with a severe injury TSH levels remained low for the first 7 days following the injury. T3 levels remained low in those with a severe TBI throughout the study; however, T4 levels appeared to be unchanged in all groups regardless of the level of injury. Growth Hormone Deficiency

What is the clinical presentation of growth hormone deficiency post ABI?

1.    Sleep disturbances

2.    Energy loss, fatigue, attention/concentration disorders, no self-esteem, poor  quality of life, headaches, decrease in cognitive performance, depression, irritability, insomnia

3.    Muscle wasting, decrease lean body mass, weight gain (visceral obesity), dyslipidemia, osteoporosis

4.    Decrease VO2max, atherosclerosis, HBP, fatigability, decrease in exercise tolerance.

5.    Routine endocrine testing should be conducted on TBI patients throughout their recovery as deficiencies may impair recovery.

Although growth hormone deficiency (GHD) is not uncommon following an ABI, it is not as quickly diagnosed as other hormone deficiencies 2. Often GHD escapes detection for months or year post injury. Symptoms of growth hormone deficiency include fatigue, decreased muscle mass, osteoporosis, exercise intolerance, dyslipidemia and truncal obesity as well as a number of cognitive deficits and a poorer quality of life 15;18.

Leiberman et al. 2examined at the prevalence of neuroendocrine disorders in those who had sustained a TBI and noted that GHD was diagnosed in 7 of the 48 patients tested. To diagnose GHD deficiencies the authors used glucagon and L-dopa stimulation tests as the majority of patients were diagnosed with a severe TBI. Further testing (IGH-I testing) was also conducted confirming the presence of GHD in these 7 patients. Of the initial 70 patients who participated, early morning cortisol levels were lower in 46%. In 15 patients, blood work revealed TSH or FT4 levels were below the normal range. Overall, 36 patients had a single abnormal axis, while 12 were diagnosed with two abnormalities. The remaining 22 patients were found to have no abnormalities 2. Given these abnormalities can impair recovery, the study authors recommended the routine testing of TBI patients. Gonadotropine Deficiency/LH-FSH Deficiency

How does gonadotropine deficiency present itself?

1.    Hypogonadism – oligomenorrhea, amenorrhea, infertility, sexual dysfunction, decreased libido\muscle atrophy, osteoporosis, loss of hair

2.    Reduced tolerance to exercise

3.    Decreased memory and cognitive performance

4.    Despite the knowing how gonadotropine deficiency present, there is very little evidence suggesting possible treatments post ABI.

Hypogonadism is often one of the earliest symptoms of hypopituitarism in those who survive a TBI 54. For males it is important to monitor testosterone concentrations as low levels in the absence of elevated luteinizing hormone (LH) levels may indicate hypogonadism. In premenopausal women monitoring estradiol levels is important. Low levels of estradiol in the absence of elevated follicle stimulating hormone (FSH) may be a sign of hypogonadism. In both genders hypogonadism has been associated with sexual dysfunction, reduced vigour, mood disorders, insomnia, loss of facial, pubic and body hair, osteoporosis and infertility 15;55. Testosterone deficiencies in males and estradiol deficiencies in women may also be a sign of hypogonadism.

There appears to be some uncertainty as to when to test for hypogonadism post injury. Due to uncertainty around the time when neuroendocrine disorders appear and disappear post injury, Hohl et al. 55, suggest testing TBI patients at least one year after injury for hypogonadism. Agha and Thompson 56suggest testing 3 to 6 months post injury, with follow-up testing at 12 months.

Two studies have examined the development of hypogonadism post ABI. Kleindienst et al. 57reported gonadotropic dysfunction was found in both genders. Deficiencies were noted in 13% of patients upon admission to hospital. Twenty more patients were diagnosed with a deficiency within the first week post injury. Study results also indicated that those who had sustained more severe injuries had either lower testosterone levels or luteinising hormone levels. In an earlier study, Lee et al. 54found similar results. In their study of males who had sustained a TBI, all were found to have altered levels of testosterone post injury. Fourteen of the twenty-one participants had an abnormally low serum concentration of testosterone, while the remaining 7 had levels towards the lower end of the normal range.  Hyper/Hypoprolactinemia

Hyperprolactinemia has been shown to be present in more than half of ABI patients in the early acute phase and it is believed that symptoms may be present in 30% of patients diagnosed with hyperprolactinemia 19. Kilimann et al.58found males had higher levels of prolactin than females and more males were found to have hyperprolactinema than females. Of note, all patients with hyperprolactinemia had either an infection, were hypoglycemic, or were on dopamine antagonists, GABA agonists, opiates or central catecholamine depletors. All of these medications are known to increase prolactin levels.

How does ACTH deficiency present clinically?

1.    Fatigue, weakness, anorexia, nausea, vomiting

2.    Decrease hair

3.    Low blood pressure

4.    Hypoglycaemia

5.    Absence of hyperpigmentation (only present in primary ACTH deficiency (Addison Disease))

6.    Maybe life threatening if acute.

The ACTH secretion tends to fluctuates at night and increase with stress, physical activity and chronic disease. The symptoms of ACTH can include weakness, nausea, fever and shock, weight loss, hypotension, hypoglycemia,hyponatremia, myopathy, anaemia, eosinophilia and limited energy output 15. Cortisol levels taken in the morning are low and there is a poor cortisol response to ACTH stimulation 18. Thyroid-Stimulating Hormone Deficiency (TSH)

What is the clinical presentation of TSH deficiency?

·         Fatigue, anemia

·         Paleness, cold intolerance

·         Muscle atrophy/cramps

·         Weight gain, depression

·         Loss of outer 1/3 of eyebrow, coarse hair

·         Coarse voice, macroglossia

·         Pre-orbital oedema

·         Bradycardia

·         Constipations

·         Neuropsychiatric disorders (hallucinations, delirium)

Thyroid-stimulating hormone (TSH) deficiency appears to be less common than other hormonal deficiencies post ABI 4. A decrease in thyroid function may lead to a decrease in an individual’s basal metabolic rate, cognitive function, memory and an increase in levels of fatigue 59. In children TSH deficiencies may lead to growth retardation 60. Individuals may also present with bradycardia, hypotension, myopathy, neuropathy, changes to the skin, hair and voice, and myxedema; however many of these symptoms do not present themselves until much later in an individual’s recovery period 15.

Diagnosing TSH has been shown to be more difficult as the symptoms are often masked by other hormonal deficiencies post ABI.TSH is often treated with levothyroxine (1 mg orally before breakfast) 61.