9 - Neuroendocrine Disorders Following

Acquired Brain Injury

Genevieve Sirois MD, Jo-Anne Aubut BA, Lilia Golverk MD, Robert
Teasell MD FRCPC, T. Arnold Bayley, MD, FRCPC, Mark Bayley
MD, FRCPC

1
 Table of Contents

9.1 History and Epidemiology ........................................................ 7

9.1.2 Association with Severity ..................................................................... 9

9.2 Pathophysiology of Hypopituitarism Post ABI ....................... 9

9.2.1 Vascular Blood Supply of the Pituitary Gland .................................... 9
9.2.2 Mechanism of Injury .............................................................................. 9
9.2.3 Injuries Associated with TBI ............................................................... 10
9.2.4 Isolated & Combined Hormone Deficiencies .................................... 10

9.3 Anatomy of the Neuroendocrine System .............................. 11

9.3.1 Anatomy of the Pituitary Gland .......................................................... 11
9.3.2 Hormones Involved with the Neuroendocrine System ..................... 12

9.4 Neuroendocrine Laboratory Testing ...................................... 13

9.4.1 Diagnosis ............................................................................................. 13
9.4.2 Screening for Hypopituitarism Post ABI ........................................... 14
9.4.4 Neuroimaging ...................................................................................... 15
9.4.5 Provocative Testing............................................................................. 16

9.5 Physiological Disorders......................................................... 18

9.5.1 Posterior Pituitary Dysfunction .......................................................... 18
9.5.1.1 Antidiuretic Hormone Dysfunction (ADH) ......................................... 18
9.5.1.2 Syndrome of Inappropriate Secretion of ADH (SIADH) .................... 19
9.5.1.3 Hyponatremia................................................................................... 20
9.5.1.4 Diabetes Insipidus........................................................................... 23
9.5.2 Anterior Pituitary Dysfunction ........................................................... 25
9.5.2.1 Growth Hormone Deficiency ............................................................ 29
9.5.2.2 Gonadotropine Deficiency/LH-FSH Deficiency ................................ 30
9.5.2.3 Hyper/Hypoprolactinemia ................................................................. 32
9.5.2.4 Adrenocorticotropic Hormone Deficiency (ACTH) ............................ 32
9.5.2.5 Thyroid-Stimulating Hormone Deficiency ......................................... 32

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9.6 Treatment ................................................................................. 33
9.6.1 When to Begin Treatment Post ABI ................................................... 33
9.6.3 Immediate Hormone Replacement Therapy (HRT) ........................... 33
9.6.4 Gonadal Steroid Therapy .................................................................... 33
9.6.4.1 Androgen Replacement in Men or Testosterone Therapy ............... 33
9.6.4.2 Estrogen Replacement in Women ................................................... 34
9.6.5 Growth Hormone Replacement Therapy ........................................... 34
9.6.6 Replacement Therapy for SIADH........................................................ 34
9.6.6.1 Conivaptan Hydrochloride ................................................................ 34
9.6.7 Treatment of Diabetes Insipidus ........................................................ 34
9.6.7.1 Desmopressin (DDAVP) .................................................................. 34
9.6.8 Secondary Adrenal Insufficiency ....................................................... 35
9.6.8.1 Hydrocortisone ................................................................................. 35
9.6.9 Summary of Treatment........................................................................ 35

9.7 Conclusions ............................................................................. 35

Reference List ............................................................................... 38

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List of Common Abbreviations

ADH Antiduretic Hormone

AI Adrenal Insufficiency
APH Anterior Pituitary Hormones
ARG Arginine
ACTH AdrenoCortico Tropic Hormone
CAR Cortisol Awakening Response
CR Cortisol Response
CSWS Cerebral Salt-Wasting Syndrome
DHEAS Dehydroepiandrosterone Sulfate
DI Diabetes Insipidus
FSH Follicle-Stimulating Hormone
GH Growth Hormone
GHD Growth Hormone Deficiency
GHI Growth Hormone Insufficiency
GHRH Growth Hormone-Releasing Hormone
GnRH Gonadotropin-Releasing Hormone
GST Glucagon Stinulation Test
HRT Hormone Replace Therapy
ITT Insulin Tolerance Test
IGF Insulin-like Growth Factor I
IGFBP Insulin-like Growth Factor Binding Protein
LH Luteninizing Hormone
PRL Prolactin
PTHP Post-Traumatic Hypopituitarism
RAI Relative Adrenal Insuffiency
SRIH Somatostatin
SIADH Syndrome of Inappropriate Anditiuretic Hormone
SST Short Synacthen Test
TSH Thyroid-stimulating Hormone
TRH Thyrotropin-Releasing Hormone
VO2 Maximal Oxygen Uptake
WDT Water Deprivation Test

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 Table Directory

Table 9.1 Clinical Presentation of Hypopituitarism

Table 9.2 Vascular Supply of the Pituitary

Table 9.3 Potential Hypothalamic-Pituitary- Adrenal (HPA) lesions associated

with Traumatic Brain Injury

Table 9.4 Types of Injury

Table 9.5 Isolated and Multiple Pituitary Axes Affected (%)

Table 9.6 Hormones Produced and Released by the Pituitary Gland

Table 9.7 +RUPRQH5HOHDVHGDQGWKH%RG\¶V5HVSRQVH

Table 9.8 Hormonal Testing Post ABI

Table 9.9 Tests of Pituitary Function

Table 9.10 Hormone Delivery and the Effects of Insufficiency

Table 9.11 Syndrome of Inappropriate Secretion of ADH (SIADH) post TBI

Table 9.12 Hyponatremia Post ABI

Table 9.13 Diabetes Insipidus Post TBI

Table 9.14 Anterior Pituitary Insufficiency Post ABI

Table 9.15 Clinical Presentation of Growth Hormone Deficiency

Table 9.16 Presentation of GHD post ABI

Table 9.17 Presentation of Gonadotropine Deficiency

Table 9.18 Gonadotropic Dysfunction Post ABI

Table 9.19 Presentation of ACTH Deficiency

Table 9.20 Presentation of TSH Deficiency

Figure 9.1 Pituitary Gland: Normal Condition and Post Traumatic Condition

Figure 9.2 Diagram of Hypothalamic-Pituitary Axis

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 Key Points

Severe ABI patients are more likely to develop SIADH

Reducing the fluid intake of patients has been shown to be effective in treating
SIADH post ABI.

Administering saline or oral salt appears to be an effective treatment for

hyponatremia post ABI.

Insulin-like Growth Factor I (IGF-I) given post injury has been found to improve
outcomes in ABI patients; however, there is a limited amount of research
available.

Patients diagnosed with a moderate to severe ABI should be tested frequently

post injury as hypopituitarism can negatively influence recovery.

Routine endocrine testing should be conducted on TBI patients throughout

their recovery as deficiencies may impair recovery.

Evidence has shown that an ABI can affect gonadropic function; however there
is very little evidence regarding possible treatments post injury.

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9 ± Neuroendocrine Disorders Following Acquired Brain
Injury
9.1 History and Epidemiology
Neuroendocrine disorders, primarily hypopituitarism, was first diagnosed by the
German researcher Cyran in 1918 (Benvenga, 2005; Lieberman et al., 2001;
Makulski et al., 2008). Until recently damage to the hypothalamus and pituitary
gland following trauma was often not diagnosed until the post mortem
examination (Yuan & Wade, 1991). Recent research indicates neuroendocrine
disorders vary post traumatic brain injury (TBI) (Sandel et al., 2007) and what
was once thought to be a rare occurrence is now increasingly diagnosed
(Bondanelli et al., 2005; Ghigo et al., 2005; Benvenga, 2005). In the early
¶VWKHLQFLGHQFHRIK\SRSLWXLWDULVPSRVWLQMXU\ZDVWKRXJKWWREH
however, the rate has recently been quoted between 20 and 70% (Sirois, 2009,
Makulski et al., 2008). In a recent review of the literature, Schneider et al. (2007)
found the pooled prevalence of hypopituitarism was 27% post TBI and 47% post
stroke. In a study by Lieberman et al. (2001), the prevalence of neuroendocrine
dysfunction among study participants was found to be high. The pituitary gland is
most often affected with dysfunction occurring at the hypothalamic stalk or
pituitary level.
Blood and urine analysis are the most common means used to diagnose
neuroendocrine disorders. Disorders can be seen in the early days post injury,
while the patient is still in the acute stage of recovery, or in the later subacute
stage. Overall, neuroendocrine abnormalities, hypopituitarism and growth
hormone deficiencies are common among those with TBI, especially those who
have sustained moderate to severe injuries (Popovic et al., 2005).
Figure 9.1 shows the pituitary gland Figure 9.1 Pituitary Gland: Normal Condition and Post
under normal conditions (9.1a and b) Traumatic Condition
and how it can suffer injury during
and following a traumatic injury
(9.1c).

9.1.1 Signs and Symptoms

Neuroendocrine dysfunction may be
seen as temperature lability,
disturbances in appetite, weight
fluctuations, hypothalamic and
pituitary disorders, disorders of fluid
regulation, hypertension or
hypotension, fatigue, increased
anxiety, depression, memory failure, cognitive deficiencies, reduced bone and
muscle mass and immunologic disorders (Sesmilo et al., 2007; Sirois, 2009) (see
Table 1).

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Table 9.1 Clinical Presentation of Hypopituitarism

Fatigue,
Sleep Disturbance
Decreased muscle mass, increased fat mass,
Reduced exercise tolerance and muscle strength,
Amenorrhea, decreased libido, erectile dysfunction,
Decreased cognitive function, concentration, memory,
Mood disturbances, depression, irritability,
Social isolation, decreased quality of life.

Neuroendocrine disorders post TBI result from specific injuries to those areas
that regulate physiological functions in various regions of the brain, specifically
injuries along the hypothalamic-pituitary axis (Sandel et al., 2007). Symptoms
will vary depending on the area of the brain that has been affected by the injury.
Current research suggests that anyone who suffers a brain injury (whether the
result of a stroke or a traumatic brain injury) and has a GCS between 3 and 12
should be tested for hormonal disorders or deficiencies (Behan et al., 2008).
Some discretion needs to take place in those patients with the most severe
disability (vegetative state) (Sesmilo et al., 2007). Individuals at greatest risk for
post-traumatic hypopituitarism (PTHP) are those who have sustained a diffuse
axonal injury, a basal skull fracture, or who were older at the time of injury.
Length of stay in ICU, longer hospitalization and a prolonged loss of
consciousness may also play a role in the development of hypopituitarism (Klose
et al., 2007).

In the acute phase, very early hormonal alterations may reflect adaptive
responses to injury and critical illness and are not necessarily associated with
long-term PTHP. Various studies have shown that the majority of patients with
low grade or isolated deficiencies recover during the first 6 months post injury
and tend to have a much better prognosis than those who do not recover
(Bondanelli et al., 2004; Aimaretti et al., 2005; Aimaretti et al., 2004). In one
study, 5.5% of patients who showed no signs of PTHP deficiencies at 3 months
did so later at 12 months. The same study showed that 13.3 % of patients who
demonstrated isolated deficiencies at 3 months developed multiple deficiencies
at 12 months (Aimaretti et al., 2005). Growth hormone deficiency has been
shown to be the most common deficit (Bondanelli et al., 2004; Aimaretti et al.,
2005)

Due to the nature of its features and the delay of its presentation, hypopituitarism
may be missed following a stroke or an ABI (Schneider et al., 2007); thus, the
diagnosis of hypopituitarism following an ABI remains a challenge. Some of the
key indicators, such as low serum-like growth factor, may already be low in older
patients due to normal aging. Studies looking at this issue to date indicate TBI
severity, as measured by the GCS or EEGs, is not an accurate indicator of the
likelihood of developing hypopituitarism. There is however, a trend to show an
association with TBI severity (Sirois 2009).

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9.1.2 Association with Severity
There is as of yet no clear association of the development of PTHP with the
severity of TBI, the type of accident or the type of injury. Although it has been
shown by several researchers that PTHP patients had significantly lower GCS
than unaffected survivors (Sirois, 2009, Bondanelli et al., 2001; Klose et al.,
2007); this has not been a consistent finding (Aimaretti et al., 2005; Bondanelli et
al., 2007). The incidence of skull fractures and neurosurgical procedures has
been reported to be similar in patients with hypopituitarism when compared to
those with normal pituitary function (Bondanelli et al., 2007).

Benvenga et al. (2000) have noted that hypopituitarism post TBI is primarily a
disorder seen much more often with male survivors between the ages of 11 and
39 years. This is likely related to the fact that greater number of younger males
tend to sustain head injuries more often. Currently there is no evidence that
specific types of head injuries are more likely to lead to hypopituitarism (Ghigo et
al., 2005). Due to the life threatening consequences associated with pituitary
dysfunction, it represents a negative prognostic factor (Benvenga et al., 2000).

9.2 Pathophysiology of Hypopituitarism Post ABI

9.2.1 Vascular Blood Supply of the Pituitary Gland
Early investigations of the pituitary gland have shown that the majority of the
JODQG¶VEORRGVXSSO\FRPHVIURPWKHORQJK\SRSK\VHDOYHVVHOV (Stanfield, 1960).
The inferior hypophyseal artery supplies blood to the entire neurohypophysis and
to a small section of the adenohypophysis (see Table 9.2) (Behan et al., 2008;
Sirois, 2009).

Table 9.2 Vascular Supply of the Pituitary (Sirois, 2009)

Anterior Pituitary
a) Superior hypophyseal artery
- Branch of internal carotid
b) Capillary plexus formation with portal vessels
- Primary and secondary
- Run down in the stalk with 2 long portal vessels
c) 90 % of the anterior lobe is nourished by the portal system
Posterior Lobe
a) Supply by inferior hypophyseal artery
b) Short portal vessels
c) 1 capillary plexus

9.2.2 Mechanism of Injury

An anterior pituitary infarction may be caused by compression of the pituitary
gland, the hypothalamus or interruption of the long hypophyseal vessels. This
may be the result of direct trauma (skull fracture) or oedema, haemorrhage,
raised intracranial pressure or hypoxic shock. Direct mechanical injury to the
hypothalamus, the pituitary stalk or the pituitary gland may also result in
hypopituitarism. An infarction of the posterior lobe can be avoided if the inferior
hypophyseal blood vessels are not transected when the pituitary stalk is

9
ruptured. Diabetes insipidus often occurs as the result of inflammation and
edema around the posterior pituitary gland; however, this has been shown to
improve with time (Behan et al., 2008).

9.2.3 Injuries Associated with TBI

Potential lesions associated with traumatic brain injury are shown in Table 9.3.
The types of injuries are listed below in Table 9.4.

Table 9.3 Potential Hypothalamic-Pituitary-Adrenal (HPA) lesions associated with

Traumatic Brain Injury (Sirois, 2009)
Lesion Causes of Injury Location of Injury
Traumatic lesion of the stalk
Acceleration- deceleration Anterior lobe necrosis
Primary Lesion (direct) Posterior lobe haemorrhage
Basal skull fracture Direct lesion to pituitary, stalk
or hypothalamus
Brain oedema
Hypoxia
Secondary lesion (non direct) Increase intracranial pressure
Haemorrhage
Inflammatory mediators

Table 9.4 Types of Injury (Benvenga et al., 2000)

Type of Injury Percentage
Haemorrhage of hypothalamus 29%
Haemorrhage of posterior lobe 26%
Infarction of anterior lobe 25%
Infarction of posterior lobe 1%
Stalk resection 3%

In 7% of cases, neuroendocrine disorders are not associated with neuroimaging

abnormalities. The gold standard for neuroendocrine dysfunction is serum testing
tests assessing hormonal function (Benvenga et al., 2000).

9.2.4 Isolated & Combined Hormone Deficiencies

Although early hormonal abnormalities are not necessarily associated with long-
term PTHP (Klose et al., 2007), the most common problem following TBI is a
single axis or hormonal insufficiency. Research has shown that chronic hormone
deficits occur in 30 ± 40% of patients following ABI with more than one deficiency
occurring in 10 ± 15% of the population (see Table 9.5) (Kelly et al., 2000;
Lieberman et al., 2001; Aimaretti et al., 2004; Bondanelli et al., 2004). Among
individuals with an ABI growth hormone deficiencies may be seen in 20% of
those injured; gonadal hormone deficiencies in another 15%-30%, prolactin
elevation in 30% and hypothyroidism in 10%±30% of the population. Chronic
adrenal insufficiency and diabetes insipidus (DI) post ABI occurs much more
commonly, especially in those with a severe TBI (Powner et al., 2006; Bernard et
al., 2006).

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Table 9.5 Isolated and Multiple Pituitary Axes Affected (%)
Post traumatic phase 1 axis (single deficiency) 2 or more (multiple
deficiencies)
Acute 48% 28%
3 months 6.5% 6.5%
12 months 4.3% 6.5%

9.3 Anatomy of the Neuroendocrine System

Post-traumatic neuroendocrine disorders involving the pituitary gland can be
divided into posterior or anterior pituitary dysfunction depending on which
anatomical area is involved.

9.3.1 Anatomy of the Pituitary Gland

The pituitary gland consists of two lobes derived from 2 different embryological
pouches.
Anterior lobe (or adenohypophysis)
Posterior lobe (or neurohypophysis)

The pituitary gland is connected to the hypothalamus through the pituitary stalk
and controls both homeostasis and endocrine function.

The anterior lobe contains glandular cells which Figure 19.2 Diagram of Hypothalamic-Pituitary
Axis
secrete hormones into circulation. It is
controlled by the hypothalamus through the
vascular portal system. The posterior lobe
contains the axons and nerve terminals of neurons
which have their cell bodies in the hypothalamus.

The anterior lobe is responsible for the

production of six important hormones which are
secreted into the circulatory system (Blumenfeld,
2002). The six hormones produced include:
Adrenocorticotropic hormone (ACTH)
Growth hormone (GH)
Thyroid stimulating hormone (TSH)
Luteinizing hormone (LH)
Follicle stimulating hormone (FSH)
Prolactin

These hormones serve to regulate endocrine systems in other areas of the body
and are under control of hypothalamic releasing factors.

Hypothalamic releasing factors correspond with the hormones released by the

anterior pituitary and include:
Growth hormone releasing hormone Æ growth hormone release
Somatostatin Æ decreases release of growth hormone

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 Thyrotropic releasing hormone Æ thyroid hormone release
LHRH/GnRH Æ FSH and LH release
Corticotropic releasing hormone Æ ACTH release
Prolactin releasing factor (PRF) and throtropin-releasing hormone (TRH)
Æ prolactin

The posterior lobe is responsible for the secretion and storage of 2 hormones:
Vasopressin (or antidiuretic hormone (ADH)) promotes water retention in
the kidneys, which allows for concentration of urine.
Oxytocin allows for milk let down in the breast and causes uterine
contractions during labour.

9.3.2 Hormones Involved with the Neuroendocrine System

Following an ABI/TBI changes may be noted in hormones released by the
pituitary gland (Popovic et al., 2005). Hormones released include:
Table 9.6 Hormones Produced and Released by the Pituitary Gland
Glands Hormones

Anterior pituitary ACTH (AdrenoCorticotropic Hormone or Corticotropin)

Posterior pituitary
Hypothalamo-pituitary
Gonads Glands
(Ovaries or Testes)
TSH (Thyroid-Stimulating Hormone or Thyrotropin)
PRL (Prolactin or Luteotropic hormone (LTH)
GH (Growth Hormone)
FSH (Follicle-Stimulating Hormone)
LH (Luteinizing Hormone)
Oxytocin
ADH (AntiDiuretic Hormone or Vasopressin)
Gonadotropins:
LH (Luteinizing Hormone)
FSH (Follicle Stimulating Hormone)
HCG (Human Chorionic Gonadopropin)
Testosterone
Estradiol
Antimullerian Hormone
Progesterone
Inhibin B and Activin

The following table (Table 9.7) lists those hormones that are released by both the
anterior or posterior pituitary glands and WKHERG\¶VUHVSRQVHWRWKLV

Table 9.7 Hormone Released and the Body¶V5esponse

Glands Hormones Part of Body Affected Body
Response
Anterior Prolactin milk lactation
Pituitary producing
cells in breast

Adrenocorticotrophic adrenal gland adrenalin

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 Hormone (ACTH)

Growth Hormone (GH) body cells growth

(Somatotropin)

Thyroid Stimulating thyroid stimulation of

Hormone (TSH) growth and
metabolism

Follicle- Stimulating androgen

Hormone (FSH) production
testes (male sex
hormones) and
sperm
production.
testosterone
secretion

Luteinizing Hormone egg production,

(LH) estrogen and
progesterone
ovaries secretion

Posterior Antidiuretic Hormone kidney regulation of

Pituitary (ADH) water levels

Oxytocin uterus labour

contractions

9.4 Neuroendocrine Laboratory Testing

9.4.1 Diagnosis
Diagnosis is based on clinical evaluation, laboratory testing and neuroimaging.
According to Sesmilo et al. (2007) baseline hormonal testing (see Table 9.8)
should be performed in all patients; however, there is some dispute in the
literature as to when it should be completed (how soon after injury), how often
and who should be tested. As mentioned previously, clinical assessment of
hypopituitarism is difficult because the signs and symptoms are often nonspecific

13
and often mimic the neuropsychological sequelae of TBI. It is therefore
reasonable to consider performing baseline hormonal evaluation in more severe
TBI or SAH patients. Early post injury the most important anterior hormones to
screen may be thyroid, growth and Adrenocorticoid axes as these will lead more
quickly to symptoms that may affect recovery although baseline testing of all
hormones allow more easy clinical follow-up.

Table 9.8 Hormonal Testing Post ABI

Pituitary- Male Patients: LH, FSH and testosterone are used to evaluate the pituitary
Gonadal Axis gonadal axis.
Female Patients: for those who have irregular cycles LH, FSH, and estradiol
needs to be measured (Sesmilo et al., 2007).
Pituitary-Adrenal The cut off values used for diagnosing adrenal insufficiency is different in the
Axis acute phase following a TBI than in the rehabilitation phase. Pituitary-adrenal
evaluations are best performed with early morning plasma cortisol
measurements. Or 24 hour urinary free cortisol (Sesmilo et al., 2007).
Pituitary-Thyroid It has been suggested, baseline testing should include thyroid function tests
Axis (TSH, fT4, fT3) and repetition of testing where appropriate (Sesmilo et al.,
2007).

9.4.2 Screening for Hypopituitarism Post ABI

Hypotituitarism is a common and treatable condition resulting from an ABI.
Guidelines for screening patients who have sustained an ABI or a stroke include:
severity of injury, location of injury (those with basal skull fractures, diffuse axonal
injury, or increased intracranial pressure), GSC (especially those who score
between 3 and 12), length of time spent in the intensive care unit (ICU) and the
amount of time that has passed since the injury occurred (Schneider et al.,
2007).

Because hypotituitarism can evolve over time post injury, it is important to begin
screening as soon as possible. In the acute stage, due to its life threatening
potential, screening for adrenal insufficiency is important (Bernard et al., 2006).
During this stage of recovery, cortisol levels of less than 7.2ug/dL may indicate
adrenal insufficiency. Treatment should also be considered and initiated in those
cases where hyponatremia, hypotension and hypoglycaemia are present and
cortisol levels are between 7.2 and 18ug/dL (Schneider et al., 2007). For those
who have extended stays in the ICU and increased intracranial pressure, diffuse
axonal injury, or basal skull fractures assessing pituitary function may be
necessary and should be considered. While in the acute stage of recovery it is
not necessary to assess growth, gonadal or thyroid hormones as there is no
evidence to suggest supplementation of these hormones during this phase is
beneficial (Schneider et al., 2007; Ghigo et al., 2005); however, during the post
recovery stage, at 3 and 6 months, a clinical assessment for hypopituitarism
should be completed (Powner & Boccalandro, 2008; Powner et al., 2006;
Schneider et al., 2006). This is especially important if any of the following are
noted: loss of secondary hair, impaired sexual function, weight changes,
polydipsia, or amenorrhea.

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For mild TBI it has been suggested to test only patients who spend more than 24
hours in hospital, who have an abnormal CT scan, or who initially have
symptoms suggesting post-traumatic hypopituitarism.

Hormonal screening should include 0900 AM serum cortisol, fT3, fT4, TSH, FSH,
LH, testosterone in men and E2 in women, prolactin, and IGF-I. In patients with
polyuria or suspected diabetes insipidus, urine density, sodium and plasma
osmolality should also be evaluated. Low IGF-I levels strongly predict severe
growth hormone deficiency (in the absence of malnutrition). Normal IGF-I levels
may be found in patients with growth hormone deficiency; therefore, provocative
tests are necessary in patients with another identified pituitary hormone deficit.
Provocative testing is recommended if IGF-I levels are below the 25th percentile
of age related normal limits (Ghigo et al., 2005).
Figure 9.4 Screening for hypopituitarism based on severity of head injury (Estes & Urban,
2005; Sirois, 2009)

Head Injury

(TBI/SAH)

Moderate to Severe Injury Mild Head Injury

Screen for Anterior and Symptomatic Asymptomatic

Posterior Dysfunction

Screen for Posterior Monitor for

Dysfunction Symptoms

If Symptoms Develop

9.4.4 Neuroimaging
In a recent review of the literature, Makulski et al. (2008) concluded that
magnetic resonance imaging (MRI) is the preferred imaging technique for the
pituitary gland as it can readily distinguish between the anterior and posterior
lobes. An MRI allows for both visualization of structural abnormalities and indirect
imaging of the blood supply. The most common pathological findings are
haemorrhage of the hypothalamus and posterior lobe and infarction of the
anterior lobe of the pituitary (Makulski et al., 2008; Maiya et al., 2008). While

15
widely regarded as the best imaging technique, MRI may still fail to show
pathological abnormalities in some patients with post traumatic hypopituitarism
(Makulski et al., 2008).

Although neuroimaging (MRI or CT scans) can be very successful in locating

lesions within various sections of the brain, they do not reveal all. Benvenga et
al. (2000) have found 6 to 7% of those with post traumatic hypopituitarism have
no abnormalities on MRI; therefore further testing is necessary. With regards to
testing, blood tests remain for the gold standard. Benvenga et al. (2000) suggest
monitoring individuals for hypoituitarism if they are male and under the age of 40,
have sustained their injury in a motor vehicle collision, and are within the first
year of injury.

9.4.5 Provocative Testing

Growth Hormone Assessment
It has been noted that approximately 20% of those with a TBI or SAH are at risk
for severe growth hormone deficiency; therefore, to rule this out provocative
testing has been recommended (see table 9.9). Due to the expense of this test, it
is recommended when other hormonal tests, such as the IGF-I, have been
completed and only to rule out other transitory hormone deficits (Sesmilo et al.,
2007).

Insulin Growth Factor (IGF)-1

It has been suggested that a relationship exists between IGF-1 and growth
hormone deficiency; however, in a study conducted by Bondanelli et al. (2007)
no relationship was found between IGF-1 and GHD as only 30% of patients with
GHD were found to have low IGF-1 levels. This finding was supported by
previous studies (Popovic et al., 2005; Bondanelli et al., 2005), indicating that low
IGF-I does not necessarily predict GH status in those who have sustained an
ABI.

Pituitary Function Testing (Serum Cortisol, ACTH)

The diagnosis of adrenocortical insufficiency requires provocative tests in
addition to measurement of early morning basal serum cortisol levels. The
normal basal morning serum cortisol values are between 150 nmol/l to 800 nmol/l
(5.3±28.6 lg/dl). Basal morning serum cortisol <100 nmol/l (<3.6 lg/dl) is
indicative of secondary adrenocortical insufficiency; if this value is >500 nmol/l
(>18 lg/dl) adrenocortical insufficiency can be excluded. When basal serum
cortisol values are borderline, a provocative test is necessary (Auernhammer &
Vlotides, 2007).

Short ACTH stimulation test

In healthy subjects stimulated serum cortisol has been shown to be between 550
nmol/l and 1110 nmol/l (19.6±39.6 lg/dl); thus a normal response is >550 nmol/l.

16
Adrenocortical insufficiency is confirmed with a serum cortisol <500 nmol/l (18
lg/dl). Standard ACTH tests should be done 4 weeks at the earliest after pituitary
surgery (Auernhammer & Vlotides, 2007).

Insulin-Induced Hypoglycemia Test

During an insulin-induced hypoglycaemia test the top serum cortisol levels in
healthy people are between 555 nmol/l to 1,015 nmol/l (19.8±36.2 lg/dl)
(Auernhammer & Vlotides, 2007). Adrenocortical insufficiency is diagnosed
when there is a serum cortisol increase of <500nmol/l. Although this test has
been shown to be the gold standard, caution is recommended when using the
test, especially for the cardiac and epileptic patient where this test has been
found to be contra-indicated.

Metyrapone
Metyrapone has been shown to block the last step in the biochemical pathway
from cholesterol to cortisol, leading to a reduction in serum cortisol, an increase
of ACTH secretion and an increase of cortisol precursors such as 11b-
deoxycortisol. The peak serum 11b-deoxycortisol levels in healthy people range
between 195 nmol/l to 760 nmol/l. During the test, serum 11-deoxycortisol may
increase to >200 nmol to exclude adrenal insufficiency. Another variant of the
test is WKHµµPXOWLSOHGRVHPHW\UDSRQHWHVW¶¶UHTXLUHRWKHUGLDJQRVWLFFXW-offs of
serum 11-deoxycortisol levels. In order to sustain this multi-step testing patients
must be hospitalized. Metyrapone may cause gastrointestinal upset and may
lead to adrenal insufficiency (Auernhammer & Vlotides, 2007). Currently this test
is considered only if other tests are inconclusive.

Corticotropin-Releasing Hormone (CRH) Test

Responses to this test vary widely between patients. Serum cortisol may
increase to < 350 ± 420 nmol/l (< 12.5 ± 15 lg/dl) as evidence of secondary
adrenocortical insufficiency, or it may increase to > 515 ± 615 nmol/l (18.5 ± 22.0
lg/dl) excluding secondary adrenocortical insufficiency (Auernhammer & Vlotides,
2007).
Table 9.9 Tests of Pituitary Function (Auernhammer & Vlotides, 2007)
Tests Methods
Growth hormone IGF-1 is low
assessment Assess family history: looking at age related issues and weight
issues (obesity) of individual and family members
Other pituitary deficits with normal IGF
Insulin-induced Insulin (0.1±0.15 IU/kg) intravenously sufficient to cause
hypoglycemia test adequate hypoglycemia (<40 mg/dl) (<2.2 nmol/l). Blood samples
are collected for measurement of serum cortisol at ±15, 0, 30, 45,
60 and 90 min.
Metyrapone test 30 mg/kg orally at midnight with a snack to minimize
µµRYHUQLJKWPHW\UDSRQH gastrointestinal discomfort. Blood for serum 11b-deoxycortisol,
WHVW¶¶ ACTH and cortisol are obtained at 8 AM.
Corticotropin-releasing 100 µg recombinant human CRH is given intravenously. Blood
hormone (CRH) test samples for serum cortisol are collected at ±15, 0, 30, 45 and 60
min.

17
 Short ACTH stimulation test 250 µg recombinant human ACTH and serum cortisol, given
intravenously. The responses are assessed at 0, 30 and 60 min.

9.5 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 in Table 9.10.

Table 9.10 Hormone Delivery and the Effects of Insufficiency (Makulski et al., 2008) p.326
Pituitary

Anterior pituitary
Somatotrophs Lactotrophs Gonadotrophs Thyrotrophs Corticotrophs

~50% of cells ~10%-25 % of ~10%-15% of cells ~3%-5% of ~15%-20%

growth hormone cells prolactin lutenizing hormone cells thyroid of cells
(GH) (PRL) (LH) and follicle stimulating adrenocorticotrop
stimulating hormone (TSH) hic hormone
hormone (FSH) (ACTH)

Targets
Musculoskeletal Mammary gland Gonads and Thyroid gland Adrenal gland
System Ovaries
Symptoms of Insufficiency
abdominal fat lactation facial wrinkles dry skin, depression,
LDL secretion of weight, anxiety,
estrogen and depression, fatigue,
progesterone fatigue & apathy,
muscle cognitive nausea,
mass, libido deficits vomiting, & under
vigor, fertility, stress,
concentratio pubic hair & Ļcold tolerance hypoglycemia
HDL axillary hair & heart rate hyponatremia

ĻZHLJKWVWUHQJWK
& skin color
Posterior Pituitary
Oxytocin Vasopressin
Targets
Mammary gland and Uterus Kidney and Arterioles
Symptoms of Insufficiency
lactation & uterine contractions blood pressure & water retention

9.5.1 Posterior Pituitary Dysfunction

9.5.1.1 Antidiuretic Hormone Dysfunction (ADH)

Early studies investigating the impact of an ABI on the posterior pituitary gland
have demonstrated a disruption in sodium and fluid balance (Doczi et al., 1982).
Makulski et al. (2008), have noted the more common medical consequences of

18
an acute TBI are disorders of salt and water balance resulting in inappropriate
secretions of antidiuretic hormone (SIADH), hyponatremia and diabetes insipidus
(DI). Abnormalities of antidiuretic hormone represent one of the most common
endocrine disturbances that occur in patients following a TBI (Powner et al.,
2006).

9.5.1.2 Syndrome of Inappropriate Secretion of ADH (SIADH)

SIADH has been diagnosed in patients when sodium serum levels drop below
135mEg/L (hyponatremia) (Goh, 2004) coupled with an inappropriate elevation of
urine osmolality (Blumenfeld, 2002). Given that adrenal insufficiency can be life-
threatening, it should be evaluated when suspected in the acute phase (Sesmilo
et al., 2007). 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 (Sesmilo et al. 2007). It
has been suggested that the use of medications such as carbamazepine, SSRI,
diuretics, vasopressin analogs, and chlorpromazine may lead to SIADH (Agha et
al., 2005; Goh, 2004; Haugen, 2009).

Individual Studies
Table 9.11 Syndrome of Inappropriate Secretion of ADH (SIADH) Post TBI
Author/Year/
Country/ Study
Methods Outcome
design/PEDro
and D&B Score
Doczi et al., N=84 1808 patient charts were During the first week post injury, of the
(1982) reviewed. Only patients with 84 pts who developed SIADH 8.2% had
Hungary evidence of syndrome of a moderate to severe TBI. 41 patients
Chart Audit inappropriate secretion of developed symptoms of SIADH but these
antidiuretic hormone (SIADH) symptoms resolved themselves in a few
were included. Patients were days and did not require drastic fluid
given 400 to 500 ml of 5% restriction. The remaining 43 patients
dextrose in half-normal sodium developed severe SIADH and required
chloride solution every 8 hours. fluid restriction.
SIADH was diagnosed when the
following symptoms were present:
serum sodium below 134
mmol/litre, serum osmolality
below 280 mosm/kg, urine
sodium (24hrs) above
30mmol/litre and urine osmolality
higher than serum osmolality.
Born et al., N=109 Patients with severe TBI Six of the 36 patients were diagnosed 3
(1985) were included in the study and of to 4 day post injury with SIADH, the
Belgium these 36 (or 33%) developed remaining 30 were diagnosed 7 to 19
Case series hyponatremia according the lab days post injury. For those diagnosed
definition of SIADH. 5% glucose several days post injury, serum sodium
in a 0.45% saline solution at the values indicated moderate or severe
rate of 50mL/h was intravenously syndromes.

19
 fed to patients during the 3 days
post injury.

Discussion
In a review of 1808 ABI patients conducted by Doczi et al.(1982), 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
ZHUHIRXQGWRKDYHGHYHORSHGVHYHUH6,$'+3DWLHQWV¶ZHUHGLDJQRVHGZLWK
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. (1985), 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.

Conclusion

Results from two studies found those who had sustained a severe ABI
were more likely to develop symptoms of SIADH. In both studies the
authors suggested restricting fluid intake to assist in the resolution of
symptoms.

Severe ABI patients are more likely to develop SIADH

Reducing the fluid intake of patients has been shown to be effective in

treating SIADH post ABI.

9.5.1.3 Hyponatremia
Hyponatremia, defined as serum sodium concentration less than 136 mmol/L
(Gross, 2008) may 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% (Chang et al., 2008). Symptoms of hyponatremia include
lethargy, coma, or seizures. Recommendations for the treatment of
hyponatremia, resulting from SIADH, include limiting daily fluid intake. The death
rate for those diagnosed with hyponatremia is 60% higher than for patients who
do not have it.

20
Individual Studies
Table 9.12 Hyponatremia Post ABI
Author/Year/
Country/ Study
Methods
design/PEDro
and D&B Score
Zhang et al., N=68 Individuals selected
(2008) for participation had either a
China mild, moderate or severe
Case-Control TBI. This group was
compared to a group of
individuals who did not
have a TBI (n=24). In those
that were diagnosed as
having hyponatremia,
thyrotropin-releasing
hormone (TRH) was
conducted. A variety of
blood tests were
completed.
Moro et al., (2007) N=298 A review of patient
Japan charts between Jan 2003
Chart Audit and December 2004 was
conducted. Hyponatremia
was defined as serum
sodium levels below
136mEq/L.
Zafonte & Mann N=1 A 45 year old female
(1997) patient participated in the
USA following study. post injury.
Case Study
21
Outcome
When compared to the control group the
following was noted:
1) Blood osmotic pressure was significantly
lower (p<0.05) for the ABI group
2) Urine osmotic pressure was higher for the
ABI group
+
3) Na concentrations were also lower for
those in the ABI group compared to controls.
4) The incidence of hyponatremia was
significantly higher for those in the severe
ABI (GCS </=8) group (p<0.001).
+
5) Na concentrations in blood were <135
mmol/L for those with severe ABIs;
significantly lower than the levels found in
the mild to moderate ABI group (p<0.05).
6) Atrial natriuretic peptide (ANP) and brain
natriuretic peptide (BNP) were significantly
different between the control group and the
ABI group; however no significant
differences were noted when looking at the 3
ABI groups.
The study found 16.8% of the 298 patients
presented with signs of hyponatremia.
Those diagnosed with hyponatremia were
found to have a significantly longer
administration period (p<0.001) and worse
outcomes (p=0.02) than the remaining
patients. 37 of 50 patients with hyponatremia
responded to sodium supplementation;
however, 7 of these patients required further
sodium supplementation when they showed
signs of a recurrence of hyponatremia. In the
13 remaining patients hydrocortisone was
administered as sodium supplementation
therapy was ineffective. Serum sodium
levels reached normal range within a couple
of days once on hydrocortisone.
Hydrocortisone treatment allowed for the
improvement in the amount of sodium
excretion (p=0.002) and urine volume
(p=0.005) in most patients.
Patient was found to have a serum sodium
level was 121mEq/dl, with serum osmolarity
being normal and urinary serum sodium was
elevated. Fluid was restricted to 800cc per
day. To treat the vasospasm that was
diagnosed shortly afterward, the patient was
treated with aggressive hydration. Following
 this hyponatremia was noted as sodium
levels once again were found to be
121mEq/dl. Cerebral salt wasting was
established and the patient was treated with
saline both intravenously and orally. The
situation began to resolve itself within a few
days.
Chang et al., N=1 A 48 year old male Patient was treated with hypertonic saline
(2008) patient suffered a rapid (3%NaCl) and fluid restriction. Sodium levels
China drop in serum sodium improved gradually.
Case Study levels.

Discussion
Zhang et al. (2008), 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) (Zhang et al., 2008).

Moro et al. (2007) conducted 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 (1997) and Chang et al. (2008) each published case studies
where hyponatremia was present. Zafonte and Mann (1997) noted that the
SDWLHQW¶VVRGLXPOHYHOKDGGHFUHDVHGWRP(JG/VKHKDGORVWZHLJKWand
was clinically dehydrated. The patient was treated intravenously with normal
saline and oral salt supplementation. $QLPSURYHPHQWZDVIRXQGLQWKHSDWLHQW¶V
serum sodium levels within days.

Chang et al. (2008), 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

22
and after 3 more episodes of hyponatremia, sodium levels increased and
stabilized.

Administering saline or oral salt appears to be an effective treatment for

hyponatremia post ABI.

9.5.1.4 Diabetes Insipidus

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 (Tsagarakis
et al., 2005). Simply put, ',UHVXOWV³in 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
(Agha et al., 2005). Individuals suffering from DI may experience severe thirst,
polyuria and polydipsia (Blumenfeld, 2002).

Individual Studies

Table 9.13 Diabetes Insipidus Post TBI

Author/Year/
Country/
Study
Methods
design/PEDro
and D&B
Score
Hadjizacharia N=436 Patients who had sustained
et al., (2008) an ABI and were admitted to the
USA surgical unit were included in the
Prospective following study. Of the ABI patients
who entered the study, 44 (10%)
had penetrating injuries and 392
(90%) had injuries resulting from
blunt force trauma.
Agha et al., N=50 Patients were evaluated
(2005) during the acute phase of recovery,
Ireland 6 and 12 months post injury. 32
Prospective patients were found to have a
severe TBI, while the remaining 18
were diagnosed with a mild or
moderate TBI. DI was diagnosed in
the TBI group if plasma sodium
exceeded 145 mM in the presence
of inappropriately dilute urine and
polyuria of >3.51/24h.
Hatton et al., N=25 Initially 33 individuals (18 to
(1997) 59 were selected for participation
USA but 8 died. Patients were
RCT randomized into the treatment or
PEDro=5 control group. Both groups
D&B=17 received nutritional support and
Outcome
15% of patients (or 67) were diagnosed
with diabetes insipidus. Time of
admission to time of diagnosis was
approximately 1.7 days. Patients
diagnosed with DI had a significantly
higher incidence of medical
complications than those not in the DI
group (P<0.016).
During the acute phase of recovery, 13
patients were diagnosed with DI. All were
diagnosed within the first 11 days post
injury. Treatment for DI included the
administration of desmopressin, given
either subcutaneously or orally. At the
th
6 month mark 9 patients had recovered.
The remaining 4 patients continued on
the desmopressin, the 12 month follow-
up showed 3 patients continued to take
desmopressin as they continued to show
signs of DI.
Those in the control group were found to
have significantly lower MEE (p<0.01)
and higher caloric intake (p<0.02) than
those in the treatment group. In the
treatment group the average caloric
intake was 36kcal/kg/day compared to

23
 neurosurgical intensive care;
however those in the treatment
group also received insulin-like
growth factor-I for 14 days. The
following were monitored: energy
expenditure (MEE), nitrogen,
weight, serum IGFI concentrations
and glucose. Glasgow Coma Score
(GCS) were evaluated daily during
the study and Glasgow Outcome
Scores (GOS) were taken at day
15, 28 and 6 months post injury.
PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002).
D&B = Downs and Black (1998) quality assessment scale score.
that of the control group (40lcal/kg/day).
During the 14 day period of the
intervention, the WUHDWPHQWJURXS¶V
nitrogen intake decreased significantly
compared to the control group
(p<0.0002). Again when looking at
weight gain and weight lost, those in the
control group were found to have had a
weight loss of approximately 3 lbs, while
the treatment group were found to have
had a weight gain of approximately 2 lbs.
Glucose concentrations were also higher
among the control group. Serum IGF-I
concentration which were low for all
patients were elevated for all in the
treatment group but only 6 control
patients were found to have the serum
IGF-I levels increased at the end of the
study. The treatment group were able to
elevate their IGF-I levels in about 4 days
compared to 11 days for the control
group.

Discussion
In an RCT, Hatton et al. (1997) randomized 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.

Hadjizacharia et al. (2008), 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

24
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. (2005) found 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.

Conclusion

Results of the studies indicate that DI is associated with lower GCS, lower
GOS and a higher mortality rate.

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

Insulin-like Growth Factor I (IGF-I) given post injury has been found to
improve outcomes in ABI patients; however, there is a limited amount of
research available.

9.5.2 Anterior Pituitary Dysfunction

Early research indicated that damage to the anterior pituitary dysfunction (APD)
was likely to not be reported post ABI (Yuan & Wade, 1991); however, APD is
now increasingly recognized (Sandel et al., 2007). 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 (Sandel et al.,
2007). 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 (Sandel et al., 2007).

Bondanelli et al. (2007) noted 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
(Aimaretti et al., 2005; Agha & Thompson, 2006). Results also indicated that the
LH-FSH and GH axes were directly related to the high occurrence of isolated
deficiencies (Bondanelli et al., 2007). 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.

25
In a systematic review, Urban et al. (2005) concluded 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. (2005) noted 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.

The following studies monitored the function of the APD in individuals with an
ABI.

Individual Studies

Table 9.14 Anterior Pituitary Insufficiency Post ABI

Author/Year
Country/ Methods Outcome

Schneider et N=78 All patients underwent
al., (2006) hormonal and clinical
Germany assessments at 3.5 months
post injury and again at 13
months post injury. Patients
underwent a CT scan, and
hormone measurements were
taken. GCS, modified Rankin
scale scores, BMIs were
recorded for all patients.
Schneider et N=78 Patients who had
al., (2008) sustained a TBI participated in
Germany the following study. All were 14
(follow-up to weeks post injury and were
previous assessed again at 13 months
study) post injury. Patients underwent
a CT scan, and hormone
measurements were taken
Agha et al., N=104 Patients with a
2004 moderate to severe TBI ranging
Ireland in age from 15 to 65 yrs were
included. All underwent thyroid
testing 17 months post injury
First evaluation (3 months post injury):
44 of the 78 patients showed signs of
impairment of at least one pituitary axis.
15 had hypocortisolism
In 6 secondary hypothyroidism was found
Those with impaired GH secretion were
found to be older and had higher BMIs, and
lower IGF-I levels.
Second evaluation (12 months post injury):
36% continued to have hormonal
disturbances.
Those with hypopituitarism were older than
those not diagnosed with hypopituitarism.
Modified Rankin Scale scores were higher
among those with hypogonadal.
Testing at both time periods indicated that
greater diffuse axonal injury was associated
with a higher prevalence of hypopituitarism.
Hypogonadism was more frequent for those
whose TBI resulted in transient diabetes
insipidus, or whose injury was the associated
with polytrauma and/or hypoxia. t.
An anterior pituitary hormone deficiency was
found in 29 of the 102 patients studied. 10.7%
were found to be GH deficient, with 8.8%
having severe GH deficiencies. Those found to
be GH deficient also had a higher body mass
index. 12 patients (of which 10 were men) had
gonadotropin deficiency. This deficiency did not
appear to be associated with gender, BMI,
GCS, CT scan results, cerebral edema or mass
evacuations; however, it did appear to be

26

Tranriverdi N=104 Patients with mild
et al., 2007 (n=49), moderate (n=24), and
Spain severe (n=31) TBIs were
included. Hormonal testing was
conducted post injury.
Tranriverdi N=52 All patients underwent
et al., 2006 basal hormonal testing with in
Spain the first 24 hours of admission
to acute care and were
revaluated 12 months later.
Various hormonal assessments
were conducted
Tranriverdi N=30 All patients involved with
et al., 2008 the study had sustained a TBI
Spain through either traffic accidents
(follow-up to or falls. The majority of patients
2006 study) (n=19) were found to have mild
injuries and the remaining 11
SDWLHQWV¶LQjuries were found to
be moderate or severe. All
underwent various hormonal
testing.
Cernak et N=31 Individuals were divided
al., (1999) into 3 groups: group 1 mild TBIs
Yugoslavia (n=8) with no significant
neurological deficits; group 2
severe TBIs (n=10) who had
sustained severe injuries due to
a GSW to the head; group 3, 13
indirect neurotrauma patients.
Patients were then compared to
a group of normal subjects
(n=10). Blood level of
testosterone, thyroid stimulating
hormone (TSH), total
triiodothyronine (T3), throxine
(T4), and serum cortisol were
taken on all patients.
27
associated with age.
No significant differences were noted between
the age, TSH, cortisol, ACTH, FSH, LH, IGF-I,
GH and free testosterone levels between the
groups. Based on prolactin levels 19 of 97
patients had hyperprolactinemia. GCS were
negatively correlated with prolactin levels (r=-
0.26, p=0.01), positively correlated with cortisol
levels (r=0.20, p=0.04), cortisol levels were
positively correlated with ACTH levels (r=0.42,
p=0.0001). In males testosterone levels were
positively correlated to GCS (r=0.25), p=0.04).
When looking at deaths (n=20), these were
related to age and GCS. Pituitary hormone
deficiencies were noted: TSH deficiencies in
3.8%, gonadotropin in 40%, ACTH deficiency
in 8.8% of the patients.
GH levels decreased between T1 and T2, At 1
yr post injury, those who were GH deficient
were found to be older. IGF-I levels were also
found to be lower than the levels found in
patients who were GH sufficient. GH
deficiencies were not originally detected in 7 of
the 13 patients diagnosed with the problem.
ACTH deficiencies were found in approximately
19% of patients in total. In the initial ACTH
screening, deficiencies were noted in 5 patients
but at the end of one year, deficiencies were
noted in 10. Four of the original 5 had
recovered, while 9 were newly diagnosed.
Basal hormone levels were measured at 1 yr
post injury (T1) and again at the third yr post
injury (T2), with no significant differences
noted. The total testosterone and free
testosterone levels were significantly different
from T1 to T2. Total testosterone levels were
lowered in patients with a severe TBI
compared to those with a mild or moderate
TBI.
Changes in hormonal levels were more
profound in those who had sustained a severe
injury. TSH levels were elevated in those who
had sustained a mild TBI for the first 3 days
following an injury. Those with severe injuries
TSH levels remained low for the first 7 days
following the injury. T3 levels remained low in
those with a severe TBI for the entire time of
the study (7 days). T4 levels appeared to be
unchanged in all groups regardless of the level
of injury. Serum cortisol levels were also
elevated for those with TBIs.
Discussion
Study results reported Schneider et al. (2006; 2008), 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. (2006; 2008) in 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 T 3
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 in
the 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 (Tanriverdi et al., 2006). 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 (Tanriverdi et al.,
2008). Tanriverdi et al. (2008) found 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. (2007), found that basal hormone levels (cortisol, prolactin and
total testosterone (males only)) were related to severity of injury.

Agha et al. (2004) in 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) (Agha et al., 2004).

Cernak et al. (1999) found 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.

28
Conclusion

Studies have shown that those who suffer from moderate to severe TBIs
are at greater risk for developing hormonal deficiencies. This may lead to a
poorer outcome following a TBI as hypopituitarism has been shown to
negatively influence recovery.

Patients diagnosed with a moderate to severe ABI should be tested

frequently post injury as hypopituitarism can negatively influence recovery.

9.5.2.1 Growth Hormone Deficiency

Although growth hormone deficiency (GHD) is not uncommon following an ABI, it
is not as quickly diagnosed as other hormone deficiencies (Lieberman et al.,
2001). 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 (see table 9.15)
(Schneider et al. 2007; Sandel et al. 2006).
Table 9.15 Clinical Presentation of Growth Hormone Deficiency
Sleep disturbances
Energy loss, fatigue, attention/concentration disorders, no self±esteem, poor quality of life,
headaches, decrease cognitive performance, depression, irritability, insomnia
Muscle wasting, decrease lean body mass, weight gain (visceral obesity), dyslipidemia,
osteoporosis
Decrease VO2max, atherosclerosis, HBP, fatigability, decrease exercise tolerance

Individual Study

Table 9.16 Presentation of Growth Hormone Deficiency (GHD) Post ABI

Author/Year
Country/ Study
Methods Outcome
Design

Lieberman et al., N=70 Adults (both males and
(2001) females) who had sustained a
USA TBI participated in the following
Cohort study. Routine endocrine
testing was performed on all
participants. Included in these
tests were TSH, free T4, (FT4),
PRL and IGF-I, and a short
corticotropin stimulation test
(ACTH). Testosterone levels
were measured in male patients
and a menstrual history was
taken in female patients. When
possible GCS were recorded.
GCS were available for only 38
subjects, of which 32 were diagnosed
with a severe TBI. Seven of the 48
patients (14.6%) who underwent
glucagon stimulation testing were
found to be GH deficient. In the 7
diagnosed with GHD, IGF-I levels were
also lower than the remaining 41
patients. In 2 of 69 patients, free T 4 and
TSH levels were well below the lower
limit of normal. 6 subjects with normal
TSH, had low FT4, and in those with
normal FT4, 7 and low TSH. In almost
half of all subjects (n=32) basal

29
 morning cortisol levels were below
normal.

Discussion
Leiberman et al. (2001), examined 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 (Lieberman et al., 2001). Given
these abnormalities can impair recovery, the study authors recommended the
routine testing of TBI patients.

Routine endocrine testing should be conducted on TBI patients throughout

their recovery as deficiencies may impair recovery.

9.5.2.2 Gonadotropine Deficiency/LH-FSH Deficiency

Hypogonadism is often one of the earliest symptoms of hypopituitarism in those
who survive a TBI (Lee et al., 1994). 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 (see table 9.16) (Schneider et al., 2007; Hohl et al.,
2009). 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. (2009), suggest testing TBI patients at least
one year after injury for hypogonadism. Agha and Thompson (2005) suggest
testing 3 to 6 months post injury, with follow-up testing at 12 months.

30
Table 9.17 Presentation of Gonadotropine Deficiency
Testosterone and estrogen/progesterone
Hypogonadism - oligomenorrhea, amenorrhea, infertility, sexual dysfunction, decreased libido
Muscle atrophy, osteoporosis, loss of hair
Reduced tolerance to exercise
Decreased memory and cognitive performance

Individual Studies
Table 9.18 Gonadotropic Dysfunction Post ABI
Author/Year
Country/ Study
Methods Outcome
Design

Kleindienst et N=71 Both male and female
al., (2009) patients ranging in age from 18 to
Germany 87 participated in the current study.
Prospective Various blood samples and urine
samples were collected from each
participant. Glasgow Outcome
Scores (GOS) were used to assess
patients at 6 month follow-up
Lee et al., N= 21 Male patients were recruited
(1994) to participate in the study. GCS, the
China Disability Rating Scale (DRS) and
Prospective the Rancho Los Amigos Cognitive
Behavioural Scale (RLACBS) were
used to assess all participants.
Individuals had diffuse or focal brain
injuries. Testosterone, follicle
stimulating hormone (FSH) and
luteinizing hormone (LH) levels
were assessed for all participants
Gonadotropic dysfunction was noted in
both males and females. Gonadotropic
insufficiency was noted in 9 of the 71
patients upon admission to hospital; 17
patients on day three, and 13 patients
on day seven.
Testosterone levels in all 21 patients
were adversely affected by the head
trauma. Fourteen men were found to
have abnormally low serum
concentration of testosterone, 7 were
found to be toward the lower end of the
normal range. GCS scores and results
from the DRS and RLACBS were not
correlated to serum concentrations of
testosterone FSH or LH.

Discussion
Two studies have examined the development of hypogonadism post ABI.
Kleindienst et al. (2009) reported gonadotropic dysfunction was found in both
genders. Deficiencies were noted in 13% of patients upon admission to hospital.
20 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. (1994) found 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.

31
 Evidence has shown that an ABI can affect gonadotropic function;
however, there is very little evidence suggesting possible treatments post
ABI.

9.5.2.3 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 (Bondanelli et al.,
2005). Kilimann et al. (2007) found males had higher levels of prolactin than
females and more males were found to have hyperprolactinema than females. Of
note, all patients with hyperprolactinemia also either had 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.

9.5.2.4 Adrenocorticotropic Hormone Deficiency (ACTH)

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
(Schneider et al., 2007). Cortisol levels taken in the morning are low and there is
a poor cortisol response to ACTH stimulation (Sandel et al. 2006).

Table 9.19 Clinical Presentation of ACTH Deficiency

Fatigue, weakness, anorexia, nausea, vomiting,
Decrease hair,
Low blood pressure
Hypoglycemia, poor quality of life
Absence of hyperpigmentation (only present in primary ACTH deficiency (Addison Disease))
May be life-threatening if acute

9.5.2.5 Thyroid-Stimulating Hormone Deficiency

Thyroid-stimulating hormone (TSH) deficiency appears to be less common than
other hormonal deficiencies post ABI (Schneider et al., 2007). A decrease in
WK\URLGIXQFWLRQPD\OHDGWRDGHFUHDVHLQDQLQGLYLGXDO¶VEDVDOPHWDEROLFUDWH
cognitive function, memory and an increase in levels of fatigue (Elovic, 2003). In
children TSH deficiencies may lead to growth retardation (Alexopoulou et al.,
2004). Individuals may also present with bradycardia, hypotension, myopathy,
neuropathy, changes to the skin, hair and voice, and myxedema; however many
RIWKHVHV\PSWRPVGRQRWSUHVHQWWKHPVHOYHVXQWLOPXFKODWHULQDQLQGLYLGXDO¶V
recovery period (Schneider et al. 2007). 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 (Yamada & Mori, 2008).

32
Table 9.20 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,
Constipation
Neuropsychiatric disorders (hallucinations, delirium)

9.6 Treatment
9.6.1 When to Begin Treatment Post ABI
To date there is no relevant data or guidelines on when to treat, how to treat or
what medication to administer. It has been suggested that testing should begin
immediately for those individuals who have been diagnosed with a moderate or
severe ABI (Estes & Urban, 2005), and are no longer in a coma or vegetative
state. Those who sustain diffuse axonal injuries (DAI) resulting from a MVA may
be at even greater risk, regardless of the severity of injury, due to the rotational
forces which the brain is subjected to (Estes & Urban, 2005). It is reasonable to
repeat screening at a minimum 6 and 12 months post injury and again at 18 and
24 months post injury in those who had a severe injury or early diabetes
insipidus.

Conditions that require immediate treatment are ACTH, ADH, TSH and
panhypopituitarism. GHD as been shown to improve with time and may improve
as other deficiencies improve; therefore, it is not necessary to begin treatments
the moment it is diagnosed particularly if it is an isolated incidence. Also
treatment in the acute phase is not recommended for GHD as there appears to
be no benefit (Sirois, 2009). For those who sustain a mTBI and a GH deficiency
has been noted during regular blood work, but no other symptoms have
appeared, it is suggested waiting 3 years post trauma to begin treatment to see if
the condition will reverse itself. If possible, when there is clear indication of
anterior or posterior pituitary dysfunction consulting an endocrinologist is strongly
recommended (Estes & Urban, 2005).

9.6.3 Immediate Hormone Replacement Therapy (HRT)

Immediate hormone replacement therapy should be administered to patients with
confirmed isolated or severe gonadal insufficiency.

9.6.4 Gonadal Steroid Therapy

9.6.4.1 Androgen Replacement in Men or Testosterone Therapy

Although growth hormone deficiency (GHD) is not uncommon following an ABI, it
is not as quickly diagnosed as other hormone deficiencies (Lieberman et al.,

33
2001). 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 (see table 9.15)
(Schneider et al. 2007; Sandel et al. 2006).

Treatments for hypogonadism include implants (implanting of 3 to 6 pellets of

unmodified testosterone (200mg) subcutaneously every 4 to 6 months), oral
testosterone replacement therapy, intramuscular injections (of testosterone
esters), transdermal patches, transdermal gels, and buccal delivery (Nieschlag et
al., 2004). Although there are several treatments available and there are several
evidence based guidelines on when and how to treat hypogonadism, there was
no literature on how effective these treatments are within the ABI population.

9.6.4.2 Estrogen Replacement in Women

Hormone replacement therapy in women has been shown to be effective in
women during their menopausal or perimenopausal years; however, long term
treatment is not recommended due to the negative benefit-risk ratio
(Auernhammer & Vlotides, 2007). Treatment for women may include the
administration of DHEA daily or testosterone and although some success has
been found using these treatments, neither has been approved.

9.6.5 Growth Hormone Replacement Therapy

In patients where there has been a confirmed growth hormone deficiency (GHD),
the introduction of growth hormone replacement therapy has been recommended
(Auernhammer & Vlotides, 2007). The goal of therapy is to elevate serum IGF-I
levels to the mid to high range. This range will vary depending on age and
gender. Growth hormone is generally administered subcutaneously. Although
this treatment has been tested with individuals who have not sustained a brain
injury, there is no literature looking at this treatment within the ABI population.

9.6.6 Replacement Therapy for SIADH

9.6.6.1 Conivaptan Hydrochloride

Treatments for hyponatremia include fluid restriction and administration of
hypertonic saline solution. These treatments may be administered alone or with
loop diuretics (Arai, Fujimori, Sasamata, & Miyata, 2009). Conivaptan, a new
medication has been approved for use by the US-FDA to treat hypervolemic
hyponatremia, but again it has yet to be studied within the ABI population.

9.6.7 Treatment of Diabetes Insipidus

9.6.7.1 Desmopressin (DDAVP)

Diabetes insipidus has been found to be a leading cause of death in those who
sustain a severe TBI (Maggiore et al., 2009). Desmopressin has been shown to
reduce urine output and liquid intake (Alaca et al., 2002).

34
9.6.8 Secondary Adrenal Insufficiency

9.6.8.1 Hydrocortisone
Moro and colleagues found that the administration of hydrocortisone was
beneficial in reducing the amount of sodium excretion in a small group of patients
with a TBI (Moro et al., 2007). Although the risk of adverse effects appears to be
low, when administering hydrocortisone, more research is needed.

9.6.9 Summary of Treatment

Table 9.21 Endocrine Treatments Post ABI (Mitchell & Owens, 1996)
Condition Treatment Dosage
Hormone Replacement Somatropin 0.06 mg/kg subcutaneous or
Therapy (HRT) intramuscular (3x/wk)
Hypogonadism Testosterone therapy Implants
(males) Oral test therapy
Intramuscular therapy
Transdermal patches
Intramuscular injection

Estrogen therapy Short term treatment due to

(females) risks
Adrenocorticotropic Hormone Hydrocortisone 20 mg in morning and 10 mg
Deficiency (ACTH) early evening. Can be given
orally, intramuscularly, or by IV.

Prednisolone 5 to 7.5 mg per day (to be given

Thyroid-Stimulating Hormone
Deficiency
Growth Hormone Deficiency
SIADH
Diabetes Insipidus
Secondary Adrenal
Insufficiency
orally and 1 x a day).
Levothyroxine 1 mg orally before breakfast
Synthetic GH (or GHRH) 0.06 mg/kg is the maximum
is given by injection dose recommended and given
subcutaneously (either subcutaneously or
through a syringe or pen) intramuscularly 3x/week
Conivaptan Generally given intravenously.
20 mg/day. Often given for
short periods of time.
Desmopressin (DDAVP) 0.1 to 0.4 ml/day intranasally
Hydrocortisone 20 mg in the morning and 10
mg early evening. Medication
can be given orally,
intramuscularly, or by IV

9.7 Conclusions
Neuroendocrine dysfunction post ABI is more frequent than initially thought. The
prevalence varies considerably among studies and this may reflect the
inaccuracy of actual testing methods. Neuroendocrine disorders often result in a
variety of symptoms such as: temperature lability, appetite disturbances,
decreased muscle mass, sleep disturbances, decreased hair, decreased libido,
and disorders of fluid regulation, or hypertension (Sirois, 2009). With the
exception of diabetes inspidus other neuroendocrine disorders remain under

35
reported and under diagnosed. Testing should be done while the patient is in
acute care for ACTH and ADH deficiencies and then during the next 12 months
for the remaining hormones. Although TSH is not a frequent deficit in the TBI
patient GH, ACTH and LH/FSH are. Failure to diagnose these dysfunctions could
LPSDFWWKHLQGLYLGXDO¶VUHFRYHU\SURFHVVDQGLPSDFWWKHLURYHUDOOTXDOLW\RIOLIH

36
Conclusions
1. Results from both studies found that those who had sustained a
severe ABI were more likely to develop symptoms of SIADH. In both
studies the authors suggested restricting fluid intake to assist in
resolving of symptoms.

2. Results of the studies indicate that DI is associated with lower CS,

lower GOS and a higher mortality rate.

3. There is Level 2 evidence suggesting IGF-I given post ABI may

improve clinical outcomes in patients diagnosed with DI.

4. Studies have shown that those who suffer from moderate to severe
TBIs are at greater risk for developing hormonal deficiencies. This
may lead to a poorer outcome following a TBI as hypopituitarism has
been shown to negatively influence recovery.

37
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