The Management of Endocrine Dysfunction in Traumatic Brain Injury

Lucy-Ann Behan and Amar Agha

INTRODUCTION

Posttraumatic hypopituitarism (PTHP) refers to any abnormality of the endocrine hypothalamic-pituitary axis following traumatic brain injury (TBI), including anterior pituitary hormone deficiency and posterior pituitary hormone deficiency.

EPIDEMIOLOGY

Based on published prospective studies the estimated frequency of long-term PTHP is 22.7% to 68.5% [1].

PITUITARY GLAND ANATOMY AND PHYSIOLOGY

The pituitary gland is located at the base of the skull within the sella turcica, and is joined to the hypothalamus by the infundibulum. The pituitary gland, measuring 8 mm by 10 mm, receives its blood supply from the internal carotid arteries, primarily via the superior hypophyseal artery and the long hypophyseal portal vessels, which arise above the diaphragma sella, while the inferior hypophyseal artery and short hypophyseal vessels enter below the diaphragma sella. The hormones produced by the pituitary and their peripheral targets are described in Table 48.1.

TABLE 48.1 Pituitary Physiology

Pituitary Hormone	Target Gland	Result
Anterior
Growth hormone	Various end organs, liver	Mainly acts via insulin-like growth factor-1
Adrenocorticotropin hormone	Adrenal gland	Cortisol, androgens
Gonadotropins (FSH/LH)	Ovaries/testes	Estrogen/testosterone
Thyroid stimulating hormone	Thyroid gland	Thyroid hormone
Prolactin	Mammary glands	Lactation and gonadal suppression
Posterior
Antidiuretic hormone (vasopressin)	Distal nephron	Fluid and electrolyte balance
Oxytocin	Uterus and breast in females	No known role in males. Contracts pregnant uterus and contributes to lactation. No known adverse effects with deficiency of this hormone

FSH, follicle-stimulating hormone; LH, luteinizing hormone.

PATHOPHYSIOLOGY

The pathophysiology of PTHP is not completely understood. Current evidence suggests that multiple factors are involved in the development of PTHP including [2]

• Primary brain injury

Mechanical trauma may injure the gland, the infundibulum, and/or the hypothalamus.

Skull base fractures or rotational and shearing injuries may compromise the blood supply to the pituitary. The long hypophyseal vessels along the infundibulum are particularly vulnerable.

Hemorrhage into the sella turcica or into the pituitary gland may also result in direct structural injury.

• Secondary insults

Hypoxia, hypotension, cerebral edema, or anemia may all contribute to pituitary ischemia.

Medications used following TBI may also contribute to PTHP by both direct effects on the hypothalamic/pituitary axis or by direct effect on the adrenal glands or cortisol metabolism. Those at risk of PTHP may not be able to compensate for any adrenal insult or altered cortisol metabolism. Medication effects are usually transient and reversible. Agents to be aware of include opiate derivatives, phenytoin, etomidate, and high-dose pentobarbital and propofol, all of which can induce acute adrenal insufficiency.

• Note that severe brain injury is not required for the development of PTHP; several studies have demonstrated hypopituitarism following moderate TBI, mild TBI, and repetitive mild sport-related injury [3].

ASSESSMENT AND MANAGEMENT OF ENDOCRINE STATUS FOLLOWING TBI

Anterior Pituitary Dysfunction in the Acute Phase (i.e., Hours to Days Post-TBI)

• Adrenocorticotropic hormone (ACTH) deficiency

Glucocorticoid deficiency is potentially life threatening.

Suspicion should be high if any of the following are present: hypotension despite pressor support, hypoglycemia, or hyponatremia.

Morning serum cortisol less than 300 nmol/L in a subject in intensive care is inappropriately low and glucocorticoid replacement is necessary [4].

Morning serum cortisol between 300 and 500 nmol/L in a subject following TBI must be interpreted in the clinical context. Replacement should be considered if any of the features (i.e., hypotension despite pressor support, hypoglycemia or hyponatremia) are present.

Confirm the subject has received no exogenous steroids that may alter the interpretation of serum cortisol results, for example, dexamethasone.

The synthetic ACTH (Synacthen) test should NOT be used to diagnose adrenal insufficiency in the acute phase of TBI as adrenal atrophy has not yet developed; the diagnosis must be based on the aforementioned features.

• Assessment of the growth hormone (GH), gonadal, and thyroid axes are not necessary in the acute phase as there is currently no evidence to suggest replacement is beneficial.

Posterior Pituitary Dysfunction in the Acute Phase

• Diabetes insipidus (DI)

Due to antidiuretic hormone (ADH) deficiency

Defined by greater than 3 L of dilute urine (urine osmolality less than 300 mOsm/kg) in 24 hours and plasma sodium greater than 145 mmol/L

May be transient in this phase of TBI

Urine output greater than 200 mL/hr for 2 consecutive hours may be suggestive.

Electrolyte abnormalities in this setting may be life threatening.

Adequate fluid replacement and ADH replacement (desmopressin) may be required and should be adjusted according to hourly urine output response and plasma sodium.

• SIADH

Characterized by euvolemic hyponatraemia in the absence of glucocorticoid deficiency or hypothyroidism.

Plasma osmolality less than 270 mOsm/kg, urine osmolality greater than 100 mOsm/kg, and spot urinary sodium greater than 40 mmol/L.

Treat with fluid restriction to 500 mL–1.5 L in 24 hours.

Rarely, hypertonic saline infusion may be required. Note that rapid changes in plasma sodium increase the risk of cerebral pontine myelinolysis. Aim to correct sodium at a rate less than 0.5 mmol/L/hr.

• Cerebral salt wasting

A very rare differential diagnosis for hyponatraemia in the setting of TBI.

Characterized by hypovolemic hyponatraemia.

Plasma osmolality less than 270 mOsm/kg, urine osmolality greater than 100 mOsm/kg, and spot urinary sodium greater than 40 mmol/L, low central venous pressure/hypotension.

Treat with isotonic saline administration to restore euvolemia. Aim to correct sodium at a rate less than 0.5 mmol/hr.

Pituitary Hormone Dysfunction in the Chronic Phase (i.e., greater than 3 Months) After TBI

Screen all patients with moderate (Glasgow Coma Scale; GCS 9–12) and severe (GCS ≤8) TBI; screen subjects with mild TBI (GCS 13–15) if indicated based on clinical symptoms and signs.

• Glucocorticoid deficiency

Characterized by life threatening adrenal crisis, hypotension, fatigue, and recurrent infections

• GH deficiency

Impaired linear growth and abnormal body composition in children; in adults reduced lean body mass, decreased exercise capacity, reduced quality of life, impaired cardiac function, and reduced bone mineral density

• Gonadotropin deficiency

In males, testosterone deficiency is associated with reduced lean body mass, bone mineral density, erectile dysfunction, and muscle weakness. Estrogen deficiency in females leads to amenorrhea and reduced bone mineral density. Although 1.5% to 41% subjects following TBI will have chronic gonadotropin deficiency, there is no available data regarding fertility outcomes. These patients should be referred to an endocrinologist for fertility assessment.

• Thyroid stimulating hormone (TSH) deficiency

Lethargy, fatigue, and neuropsychiatric manifestations

• Diabetes insipidus (DI)

Polyuria, polydipsia, and excess thirst (in those with cognitive impairment clinicians must rely on urine output and biochemical markers to suggest this diagnosis)