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Growth Hormone Deficiency as a
Consequence of Traumatic Brain Injury

E-Newsletter No. 49

Traumatic brain injury (TBI) is an enormous problem in the United States. Every 15 seconds, a traumatic brain injury occurs leading to an estimated 5 million individuals living with the sequelae. TBI strikes the younger disproportionately. It is the leading killer and disabler of those under the age of 35. Roughly two-thirds of those injured are male, although there has been a persistent, gradual rise in the number of young females with TBI.

TBI complications cover the entire spectrum of medicine. Gastrointestinal problems such as bowel incontinence and a need for a feeding tube are not uncommon. Genital and urinary tract concerns are often seen. Respiratory and cardiovascular complications may arise.

There is an entity known as mild traumatic brain injury. Those with this disorder would say there is nothing mild about it as they often have anxiety, depression and somatic preoccupation. Although it is sometimes assumed they are hysterics or malingerers, they are often found to have organic damage if objective neuropsychological tests are completed.

In 1914 Simmonds described the first case of hypopituitarism in a woman with necrosis of the pituitary. This was followed in 1918 by the first case in the literature of hypopituitarism secondary to trauma. The numbers have increased vastly since then largely due to improved survival because of better pre-and in-hospital care. Current estimates may be low because time between trauma and diagnosis may be greater than one year or more. Individuals with brain injuries, and possibly post-traumatic hypopituitarism, are frequently lost to the brain injury medical system by then.

A summary of 367 cases of hypopituitarism published between 1942 and 1998 found over 95% were diagnosed with hypogonadism, followed by hypothyroidism, adrenal insufficiency, hyperprolactinemia, diabetes insipidus, and GH deficiency [Benvenga, et al. J. Clin. Endocrinol. Metab. 85 (2000) 1353, table 1]. It goes without saying that a summary of case reports in the literature is not a true indicator of prevalence.

However in the last few years three major studies have begun with results of two published. The first studied 22 adults with TBI. They collected information in an attempt to identify risk factors for hypopituitarism using dynamic testing of pituitary function.

Growth hormone stimulation (GHS) was assessed using the insulin tolerance test (ITT) and subnormal responses were seen in 18% of the patients. Gonadotropin-releasing hormone (GnRH) stimulation found abnormal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responses in just fewer than 25% of the cohort. More than one deficiency was seen in nearly 15% of those enrolled [Kelly, et al. J. Neurosurg. 93 (2000) 743].

Glasgow Coma Scores (GCS) of <10 and diffuse brain swelling on MRI were significant predictors of hypopituitarism. Hypotensive or hypoxic episodes were seen in all patients with GH deficiency, but did not reach significance for hypopituitarism as a whole.

The other study enrolled 70 patients with TBI. Again, they used a variety of pituitary function tests. The GH stimulation test was the glucagon stimulation test (GST) with GH deficiencies found in 15% of patients. There were low IGF-I levels seen in 19% of patients. Frankly abnormal thyroid function occurred in 22%, and low morning cortisol levels in 45%. There were no cases seen of diabetes insipidus, no hypogonadism in either gender or hyperprolactinemia [Lieberman, et al. J. Clin.Endocrinol Metab. 86 (2001) 2752]. When put together, the affected axes were GH, thyroid and cortisol. Gonadotropins, prolactin and ADH secretion were often unaffected or relatively spared.

A third, as yet unpublished study of TBI is ongoing in Italy. This uses a third test for GH secretion, GH-releasing hormone (GHRH) and arginine. As before, GH deficiency was found in 20.4% of those involved (unpublished data).

Currently the experts are unsure of the pathophysiology behind pituitary injury in TBI. The shearing forces that accompany TBI could disrupt blood flow to the pituitary, or damage or interrupt neuronal function in the midbrain, and consequently impair hypothalamic function and/or feedback mechanisms to and from the pituitary. Most studies have focused on severe TBI. However there is also an even larger group with mild brain trauma who seldom are even evaluated. Mild concussions, which do not result in loss of consciousness, may be missed. Physicians may wonder if someone comes to them with vague symptoms following a history of a mild concussive event, is it appropriate to screen them for pituitary deficiencies?

Randall J. Urban, M.D., Distinguished Chair in Internal Medicine at the University of Texas Medical Branch, suggests testing for gonadotropin deficiency by a menstrual history in women, total testosterone and FSH in men, and prolactin levels for both genders. Free T4 and TSH should be checked for thyroid function, while an a.m. cortisol and cosyntropin-stimulating hormones assesses cortisol deficiencies. Finally, GH deficiencies can be assessed by measuring serum IGF-I or by performing a GHS test of choice. “I can say that if you screen someone and find a true deficiency, then replacement therapy is warranted,” said Dr. Urban. “Where we are struggling is deciding appropriate interventions for the subtle differences we find in many patients. Are they a subset of hypopituitarism patients that we need to be aware of?”

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