Traumatic Brain Injury

Does this Patient with Traumatic Brain Injury (TBI) have Hypopituitarism?

The question for the endocrinologist when presented with a patient with traumatic brain injury (TBI) is whether the TBI has resulted in hypopituitarism, and if so, whether treating the hypopituitarism will ameliorate the patient’s condition. The patient may present in the acute or chronic phase of the illness, and considerations during the two phases are different.

In the acute phase, patients with TBI may be critically ill and in intensive care. Whether or not they exhibit signs and symptoms that reflect hypopituitarism, it is important to rule out adrenal insufficiency. In contrast, as in other severe acute illnesses, laboratory evidence of hypogonadism and hypothyroidism may be present but may be transient (i.e. due to the severity of the illness itself) and adaptive. There is no evidence that treatment of hypogonadism or hypothyroidism during acute illness improves outcome, and therefore such treatment is usually not indicated.

Hypernatremia and hyponatremia may also be present but are usually managed by the intensive care unit (with a goal of maintaining a hypernatremic milieu). However, the endocrinologist may be brought in to manage persistent diabetes insipidus or Syndrome of Inappropriate Antidiuretic Hormone (SIAD), if present.

A review of the literature in 2007 noted a 27.5% prevalence of hypopituitarisms in the chronic phase after traumatic brain Injury, including an 8.2% prevalence of adrenal insufficiency, 12.5% of hypogonadism, 4.1% of hypothyroidism, 12.4% of growth hormone deficiency and a 7.7% prevalence of multiple hormone deficiencies. TBI in the chronic phase is often characterized by significant impairment.

It is therefore important to rule out hypopituitarism as a contributing factor to the disability observed. It is also important to retest patients who were diagnosed with hypopituitarism in the acute phase of TBI, as such patients may recover hypothalamic and/or pituitary function. Specifically, the following should be ruled out and treated if present: adrenal insufficiency, hypogonadism (in females of reproductive age and males), and hypothyroidism.

Growth hormone (GH) deficiency may also be present, but interpretation of results can be complicated by obesity, and there is no consensus regarding treatment.

What Else Could the Patient Have?

It is important to note that in the chronic, ambulatory phase of the illness, there is some overlap of symptomatology between the effects of traumatic brain injury itself and hypopituitarism. This may be one reason that hypopituitarism is sometimes missed in such patients. Shared features may include fatigue, an impaired quality of life, weight gain, and abnormalities in body composition, including decreased muscle mass and increased fat mass.

Key Laboratory and Imaging Tests

Acute phase

During the acute phase of the illness, while a patient is in intensive care, it is important to rule out adrenal insufficiency. A random blood cortisol of >18 mcg/dl will rule out adrenal insufficiency if the patient is severely physically stressed, as is usually the case during this period of treatment. If the patient is less severely ill, obtaining serial 8 a.m. blood cortisol levels is a reasonable approach; again a blood cortisol of >18 mcg/dl will rule out the diagnosis. In contrast, an 8 a.m. blood cortisol of <5 mcg/dl should raise concern, and a blood cortisol level of <3 mcg/dl is diagnostic of adrenal insufficiency.

An important exception to this “rule” is in patients who are receiving oral estrogens, in whom cortisol binding globulin levels (CBG) will be increased, resulting in relatively higher total cortisol levels (which are typically measured as “cortisol”) relative to the active, or “free” cortisol present; therefore a cortisol of 18 mcg/dl in such patients may be falsely reassuring, reflecting a lower free cortisol level than in patients not taking oral estrogens. In some critically ill patients cortisol binding globulin is low, leading to low total cortisol levels. This is typically associated with serum albumin levels <2.5 g/d and can lead to over-diagnosis of adrenal insufficiency..

Another important note is that cortrosyn stimulation tests do not accurately detect acute adrenal insufficiency. This is because cortrosyn administration will stimulate adrenal release of cortisol in the absence of endogenous adrenocorticotropic hormone (ACTH ) or corticotropin-releasing hormone (CRH). The usefulness of the cortrosyn stimulation test in patients with central hypoadrenalism relies on the atrophy of the adrenal glands over a period of weeks to months due to lack of stimulation by endogenous ACTH.

The endocrinologist may be called to assist with sodium management — either because of hypernatremia or hyponatremia. In a patient with hypernatremia, the diagnosis of diabetes insipidus is made when an elevated plasma sodium is present in conjunction with a urine osmolarity of less than 300 mosmol/kg, with urine osmolarities between 300 and 600 mosmol/kg consistent with partial diabetes insipidus. A common cause of hyponatremia in TBI is SIAD.

The diagnosis of SIAD is made when a low plasma sodium is present in a euvolemic patient in conjunction with a low serum osmolality and a urine sodium of >40 meq/L in the absence of adrenal insufficiency or hypothyroidism. Of note, determining the cause of hyponatremia may be complex in patients receiving diuretics, which can result in polyuria, hypovolemia and hyponatremia. In addition, other causes of hyponatremia (including hyperglycemia, hypovolemia and pseudohyponatremia) certainly occur in this population and should be considered.

Chronic phase

During the chronic phase of the disease, it is important to rule out adrenal insufficiency, hypogonadism, and hypothyroidism, as well as to assess the sodium level and consider testing for growth hormone deficiency as follows:

1. Adrenal insufficiency should be investigated. This can be accomplished with a standard 250 mcg cortrosyn stimulation test, with blood samples at baseline, 30 and 60 minutes after cortrosyn stimulation. In most cases, a peak cortisol (at any time point) of greater than 18 mcg/dl is usually consistent with normal adrenal reserve, with the caveat, as above, that patients who are taking oral estrogens require a higher cut-off, which has not been specifically established. Obtaining serial 8 a.m. cortisol levels is also a reasonable approach, especially when cortrosyn stimulation testing is not readily available. An 8 a.m. cortisol >18 mcg/dl reflects normal HPA reserve, whereas an 8 a.m. cortisol less than 3-5 mcg/dl is diagnostic of adrenal insufficiency. Levels in between require further testing with a cortrosyn stimulation test to determine reserve in the event of a physical stressor.

Patients who were diagnosed with adrenal insufficiency during the acute phase of the illness should be retested, as there have been reports of a reversal of hypopituitarism between the acute and chronic phases of the disease. In such patients, cortrosyn stimulation testing or serial 8 a.m. cortisol levels should be performed before the patient has taken his or her short-acting or medium-acting glucocorticoid dose (hydrocortisone or prednisone). If the patient takes his/her dose before testing, the results may reflect the exogenous glucocorticoid administered, rather than the endogenous reserve.

2. Hypogonadism should be investigated in men, and in women of reproductive age. In men, it should be noted that testosterone deficiency can contribute to fatigue, depression and loss of muscle mass, in addition to decreased libido, sexual function and infertility; some of these symptoms can hamper recovery from TBI. Therefore, it is important to identify and treat hypogonadism in this population. The diagnosis is made with a morning testosterone level in the presence of low or normal gonadotropin levels [leutinizing hormone (LH) and follicle stimulating hormone (FSH)], thyroid function tests and prolactin. In obese men, a free testosterone level is important as well because a low total testosterone may simply reflect a decreased SHBG level commonly observed in obese men, whereas the free testosterone may be normal.

In women of reproductive age, prolonged hypoestrogenemia can lead to early and severe bone loss, and hypogonadism results in infertility. Hypogonadism in such women is indicated by a history of amenorrhea. In the setting of amenorrhea, secondary hypogonadism is established by low or normal gonadotropins (FSH and LH), normal thyroid function tests and normal prolactin level. An estradiol level <40 pg/ml is often also helpful in difficult cases.

3. Hypothyroidism should be investigated in all patients with TBI. It is important to note that a free T4 or free T4 index is necessary to make this diagnosis — thyroid-stimulating hormone (TSH) being unhelpful in cases of central hypothyroidism. TSH levels are usually within the normal range in patients with untreated central hypothyroidism and may be slightly elevated, but are not usually suppressed as one might expect. Therefore, a normal TSH does not rule out central hypothyroid and may be falsely reassuring. In contrast, a free T4 or free T4 index below the lower limit of normal is diagnostic of hypothyroidism.

4. Growth hormone (GH) deficiency may also contribute to fatigue, an impaired quality of life, and body composition abnormalities, including reduced muscle mass, and testing should therefore be considered. A low insulin-like growth factor 1 level in the setting of panhypopituitarism can establish the diagnosis but is not accepted by all US insurance companies for proof of the disease. In most cases, GH stimulation testing will be necessary to establish the diagnosis. A growth hormone releasing hormone (GHRH)-arginine or glucagon stimulation test are well validated.

An insulin tolerance test is the gold standard but is relatively contraindicated in patients with TBI. A well-established scientific cut-off (maximum sensitivity and specificity) for the diagnosis of GH deficiency using a growth hormone releasing hormone (GHRH)-arginine test is a peak GH of 4.1 ng/ml, and many US insurance companies use a cut-off of 5 ng/ml to determine insurance eligibility. An advantage of the GHRH-arginine stimulation test is the availability of weight-based diagnostic guidelines, as obesity itself (in the absence of organic pituitary or hypothalamic damage) is associated with reduced endogenous GH release, but GHRH is not currently available in the US. The clinically established cut-off using glucagon stimulation testing is a peak GH of 3 ng/ml – a lower peak cut-off of 1 ng/ml should be considered for overweight/obese individuals.

5. A sodium level should also be checked, and a history of polyuria, nocturia and polydipsia should be elicited, as diabetes insipidus or SIAD may be present. If hypernatremia or hyponatremia are evident, further work up to determine the etiology should be pursued. The diagnosis of diabetes insipidus is made when an elevated plasma sodium is present in conjunction with a urine osmolarity of less than 600 mosmol/kg. The diagnosis of SIAD is made when a low plasma sodium is present in a euvolemic patient with a low serum osmolality in conjunction with a urine sodium of >40, in the absence of adrenal insufficiency or hypothyroidism.

Other Tests That May Prove Helpful Diagnostically

If hypopituitarism has been diagnosed, it is important to rule out a pre-existing organic cause, such as a pituitary macroadenoma, with a brain magnetic resonance imaging (MRI). Generally, patients with TBI have had numerous brain MRIs, which can be reviewed for a pituitary or hypothalamic lesion. In the event that brain MRIs are not available for review, a pituitary protocol brain MRI should be ordered.

Management and Treatment of the Disease

Acute phase

In the acute phase of TBI in a patient in the intensive care unit, stress-dose steroids are appropriate for the patient who has adrenal insufficiency. A typical glucocorticoid stress dose is 100 mg of intravenous hydrocortisone every six to eight hours. In a patient with TBI who is not as acutely ill, lower doses of glucocorticoids should be used, tapering to a physiologic dose as soon as possible. Diabetes insipidus can be treated with subcutaneous (2 mcg) desmopressin acetate (DDAVP) as the patient likely will be unable to use a nasal spray or take an oral medication. Each subcutaneous dose should be allowed to wear off before the next is administered in this phase of the illness, as diabetes insipidus may be transient, and SIAD may subsequently develop. Sodium levels should be monitored closely to avoid overcorrection. The intensive care unit staff or neurosurgeons will often manage sodium abnormalities during this period of time and may have a goal in the hypernatremic range to minimize brain edema.

Chronic phase

1. Adrenal insufficiency: Adrenal insufficiency should be treated with the lowest effective glucocorticoid replacement dose. A reasonable starting dose of 15 mg of hydrocortisone daily in divided doses (e.g., 10 mg at 8 a.m. and 5 mg at 2 p.m) or equivalent, such as 2.5-5 mg prednisone once daily upon awakening. It is important to avoid over-replacement, which has been shown to exert adverse effects on weight, cardiovascular risk markers and markers of bone metabolism; an important retrospective study suggested an increase in mortality in patients with nonfunctioning pituitary tumors who were taking greater than or equal to 30 mg daily of hydrocortisone. Mineralocorticoid replacement therapy (fludrocortisone) is not needed for patients with adrenal insufficiency of central origin because regulation of aldosterone and other mineralocorticoids is under the control of the renin-angiotensin system, which is not affected in central hypoadrenalism. It is important to counsel patients regarding adrenal insufficiency “sick rules” and advise them to wear a Medic Alert-type bracelet or necklace at all times. Adrenal insufficiency sick rules include: 1) increasing glucocorticoid doses two to three times during febrile illness and 2) reporting to the emergency department if vomiting. If patients are amenable, they should be prescribed 100 mg injectable hydrocortisone for severe GI illness and for travel to countries where high quality medical care is not readily available. It is also important to counsel each patient to notify his/her endocrinologist and surgeon prior to scheduled surgeries.

2. Hypogonadism: In men with hypogonadism, testosterone replacement with a gel, patch or long-acting parenteral preparation (such as subcutaneous implants or intramuscular testosterone undecanoate injections) should be prescribed for those without contraindications, such as prostate cancer, and titrated within the normal male range after documentation of a normal prostate specific antigen (PSA) level. Intramuscular testosterone ester administration every 1-4 weeks can also be used, and may be preferable in patients who are unable to apply gels or patches daily or who do not have insurance coverage of the more expensive and/or long-acting preparations. However, it should be noted that the peaks and troughs in serum testosterone levels achieved are more likely to cause erythrocytosis and mood swings. Hemoglobin or hematocrit and PSA levels should be followed indefinitely in all men receiving testosterone therapy of any kind.

Testosterone therapy reduces fertility and therefore is not the appropriate therapy for men seeking fertility within the following year. Instead, gonadotropin therapy should be prescribed by a clinician with experience in this area for such men. It is important to note, however, that testosterone therapy is not an effective contraceptive, and therefore patients who are sexually active and not seeking fertility should be counseled to use a contraceptive method.

In women of reproductive age who do not have a contraindication to estrogen therapy, such as a hormonally responsive cancer, estrogen therapy should be strongly considered to protect the skeleton. Patients with a uterus should not receive unopposed estrogen. Choices for therapy include standard oral contraceptives and post-menopausal estrogen replacement regimens, such as transdermal estradiol 50 mcg daily plus oral progesterone 200 mg daily for 12 days per month. Combination estradiol/progestin patches are also now available. Ovulation induction by a reproductive endocrinologist is necessary for achievement of fertility.

Of note, hypogonadism has been shown in one study to be associated with impaired quality of life, specifically in individuals (men and women combined) with a history of TBI and in another individual with hypogonadism, who were less likely to be working and had more impaired functioning. However, the number of patients with hypogonadism included in each of these studies was small.

3. Hypothyroidism: Hypothyroidism should be treated with levothyroxine, with a goal of a free T4 in the mid-normal range, except in patients with anxiety disorders or significant heart disease, who may only be able to tolerate lower doses and in whom a free T4 in the lower-normal range is appropriate. It is important to note that TSH levels cannot be used to monitor adequacy of levothyroxine dose. This is because TSH levels decrease — often to below the lower limit of normal — in patients with hypopituitarism who are administered even very low doses of levothyroxine. Therefore, a low TSH in a patient with central hypothyroidism who is receiving levothyroxine may mislead a clinician to conclude that the levothyroxine dose is inappropriately high, when in fact it might be appropriate or even too low.

4. GH deficiency: A trial of treatment with GH in patients with GH deficiency should be considered, especially if they report signs or symptoms that could potentially respond to such treatment, such as fatigue, daytime somnolence, and decreased muscle mass. GH treatment is absolutely contraindicated in patients with cancer or a history of cancer and should be prescribed with caution and close monitoring in patients with pre-diabetes or diabetes mellitus. Typical starting doses are 0.1 to 0.4 mg daily — lower for men and higher for women of reproductive age, and highest for women of reproductive age receiving oral estrogens.

The dose should be titrated to the mid-normal age-appropriate IGF-1 range, as tolerated; typically IGF-1 levels are measured four weeks after initiating GH treatment and four weeks after any dose change. Monitoring of side effects is important and can include worsening glucose control, signs and symptoms of carpal tunnel syndrome, edema and/or arthralgias. There has been one relatively large retrospective study and several small prospective studies that have demonstrated improvements in quality of life and one small published randomized, placebo-controlled study of GH replacement in patients with TBI (n=23) which showed improvements in cognitive function in the GH compared with the placebo group. Further studies are needed to determine whether GH should be standard-of-care in patients with TBI who develop GH deficiency.

5. Diabetes insipidus: Diabetes insipidus can usually be managed with DDAVP, either by nasal spray or oral preparation. The nasal spray is more potent than the oral preparations and if given before bedtime, prevents nocturia in the majority of patients, and improves both sleep and daytime fatigue. Patients who have a thirst disorder in addition to diabetes insipidus can be very difficult to manage and usually need a prescription that specifies exact fluid intake in addition to DDAVP.

6. SIAD: Chronic SIAD can usually be managed with a mild fluid restriction in such patients.