Incidence and prevalence
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Pituitary damage because of brain trauma was first recognized in 1918 and was initially thought to be relatively rare. It has only been with increased awareness that it has been found to be more prevalent. Schneider et al reported that it occurred in approximately 27% of patients who were screened with chronic traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) and that it had an impact on functional recovery and morbidity.
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Approximately two-thirds of patients who have died from severe head injuries have been found to have structural abnormalities in the pituitary stalk, pituitary, or hypothalamus.
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In 2000, Benvenga and colleagues published a large review of posttraumatic hypopituitarism (PTH) that helped to further classify the relationship between TBI and PTH. They were able to identify hundreds of cases described in the literature and add new cases of patients identified by the authors that further recognized the presence of PTH in mild injuries and found that multiple hormonal abnormalities can occur at once.
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Although multiple hormonal abnormalities can exist simultaneously, growth hormone deficiency appears to be the most prevalent hormone deficiency in those screened 6 months or more postevent. ,
Anatomy review
The pituitary gland is a small pea-sized structure located in the base of the brain in the middle cranial fossa. It is composed of two lobes (anterior and posterior) that are connected to the hypothalamus by the infundibulum. The anterior lobe produces and secretes hormones, whereas the posterior lobe only secretes them. The posterior lobe hormones (antidiuretic hormone, oxytocin) are produced by nerve cells in the hypothalamus and then stored and secreted by the posterior pituitary. Pituitary anatomy and the essential role the hypothalamus plays in regulating pituitary function is illustrated in Figure 23.1 .
There are many theories regarding the pathophysiology behind PTH. Generally, it is believed that the unique structure of the pituitary, its anatomical location within the sella turcica, and the complex it forms with the hypothalamus through the infundibulum place it at risk for a variety of injuries. Subsequently, the pituitary is susceptible to direct injury, edema, and ischemic insult. Ischemia is felt to be a result of direct injury to the tenuous hypophyseal portal veins that supply blood to the gland and secondary effects of injury such as hypoxia and hypotension. The connection to the hypothalamus by the infundibulum makes these structures prone to shearing forces or transection in the setting of TBI. Additionally, the bony encasement of the sella turcica does not accommodate for edema that can occur postinjury, further compromising the gland.
Pituitary hormones
Anterior pituitary
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Thyroid-stimulating hormone (TSH): Thyroid function is strongly regulated by the hypothalamic–pituitary–thyroid complex. Thyrotropin-releasing hormone (TRH) is released from the hypothalamus and causes the release of TSH subunits. Mature TSH is released from the pituitary and then reaches the thyroid gland, where it stimulates thyroid hormone production and release. Figure 23.2 illustrates how thyroid hormones eventually reach the hypothalamus and pituitary, where they inhibit the production and secretion of TRH and TSH, contributing to the axis. Due to the potential confounding effects of nonthyroidal illness (sick euthyroid syndrome) and the long half-life of thyroxine, it has been suggested that screening for thyroid dysfunction can reasonably be deferred for several (>4–6) weeks after TBI—assuming there is no suspicion of prior thyroid dysfunction—and then treated if necessary.
• Fig. 23.2
Thyroid hormone regulation.
(Reprinted from Melmed S. The Pituitary. 4th ed. London, UK: Elsevier/Academic Press; 2017:23-45.)
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Adrenocorticotropic hormone (ACTH): In response to ACTH stimulation, the adrenal cortex produces three major classes of steroids: mineralocorticoids, glucocorticoids, and adrenal androgens. The adrenal androgens are responsible for secondary sexual characteristics in females. The glucocorticoids modulate metabolism and the immune responses. The mineralocorticoids are responsible for the modulation of blood pressure, vascular volume, and electrolytes and are also critical in the stress response. Acute ACTH deficiency can be life threatening and should be treated. Otherwise dynamic screening for deficiency should only be done if suspected.
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Follicle-stimulating hormone/luteinizing hormone (FSH/LH): The gonadotrophins make up approximately 10% of what? function? volume? of the anterior pituitary. In the acute phase, it has been found there is a transient suppression of gonadotropin release that typically recovers to normal levels; therefore, treatment should be considered only in the chronic phase. Decreased levels are associated with fatigue, fertility issues, and decreased bone mineral density. There may also be a link with testosterone levels and rehabilitation outcomes. Young et al, in a small retrospective study, found that low rehab admission testosterone levels correlated with longer lengths of stay and decreased Functional Independence Measure efficiency, although these findings were not significant. Although testosterone replacement can be relatively easy to treat, any suspicion of prolonged gonadotropin deficiency should be worked up in conjunction with an endocrinologist. No large studies have examined the effects of female sex hormone replacement in TBI.
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Growth hormone (GH): Long-term GH deficiency (GHD) is associated with decreased quality of life, impaired cognition, decreased lean body mass, reduced bone mineral density, and impaired cardiac function. A serum/plasma IGF-I level below the reference range for age and gender is suggestive of GHD, although it is not diagnostic. Low levels require referral to an endocrinologist for dynamic testing to investigate for GHD and coincident ACTH/cortisol deficiency. However, referral for dynamic testing of GHD in a subject with an IGF-I level in the normal range in most instances can be deferred to greater than 12 months after TBI. GH replacement would generally not be considered until this time point because spontaneous recovery may occur in some subjects.
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Prolactin (PRL): PRL induces and maintains lactation, suppresses sexual drive, and decreases reproductive function. It can be elevated because of many disease states, including TBI, and its elevation is considered a nonspecific finding. No relation has been made to prolactin levels and outcomes post TBI.
Posterior pituitary
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Oxytocin: Oxytocin stimulates milk production and is not of clinical relevance in TBI management at this time, therefore it has not been studied.
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Antidiuretic hormone (ADH): ADH is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus and stored in the secretory granules of the posterior pituitary. In response to the body’s feedback mechanism, it is then released into the bloodstream to maintain circulating blood volume and serum osmolality. It does this by promoting water reabsorption in the distal collecting tubules and collecting ducts of the kidney. Secretion of ADH is controlled by two principal negative-feedback mechanisms: osmoregulation and baroregulation. Osmoregulation is the mechanism used by the body to maintain water balance. Normal serum osmolality is 280 to 295 mOsm/kg. Even slight changes in serum osmolality can markedly affect ADH release. In general, ADH is mostly secreted based on concentration of body fluids, but in cases of severe volume depletion such as hypotension or blood loss, which can occur with TBI, baroregulation takes precedence and can cause excessive stimulation of ADH.
Diabetes insipidus (DI): Studies have shown that when diagnosed by using the water deprivation test, the prevalence of DI is as high as 26% in the acute phase and 6.9% among long-term survivors. DI is characterized by an abnormal increase in urine output, an increase in fluid intake and thirst caused by decreased secretion of ADH, resulting in elimination of extracellular fluid. In trauma patients, DI is typically caused by damage to the posterior part of the pituitary gland where ADH is stored and secreted. It has been consistently linked to more severe injuries, cerebral edema, lower Glasgow Coma Scale (GCS) scores, and higher mortality rates. The occurrence of DI has also been associated with brain death as it is present in 80% of brain-dead patients. The overall mortality ate of TBI patients with PTDI ranges between 57% to 69% and increases to 86% to 90% in those with early onset of diabetes insipidus in the first 3 days from injury.
Syndrome of inappropriate antidiuretic hormone (SIADH): Hyponatremia is the most common electrolyte abnormality in patients with neurologic problems and is particularly common after TBI; up to 33% of patients with TBI have hyponatremia at some point in their recovery. SIADH is characterized by abnormally high levels or continuous secretion of ADH, causing renal reabsorption and retention of water. Water is continually being reabsorbed by the kidneys, leading to concentrated urine, fluid retention, and hyponatremia. The treatment of SIADH is focused on fluid restriction and slow, careful replacement of sodium with an intravenous hypertonic solution of sodium chloride and/or diuretics. Medications to suppress ADH activity (demeclocycline hydrochloride) or inhibit renal response to ADH (lithium carbonate) are also options.
Cerebral salt wasting (CSW): Unlike SIADH, CSW is characterized by a true hyponatremia, specifically hyponatremia that results from a loss of both sodium and extracellular fluid. Even though ADH levels are elevated in patients with CSW, the body loses extracellular fluid and plasma volume decreases, resulting in decreased body weight (volume-contracted state). The pathophysiology of CSW syndrome is unclear but is thought to be caused by multiple mechanisms that affect sodium and water balance. It can be difficult to distinguish from SIADH, so extracellular fluid status is important to better differentiate between these two causes of hyponatremia. CSW usually requires replacement of fluid volume with physiological saline but can also be treated with hypertonic saline when more rapid correction is needed. As in treatment of SIADH, hypertonic solutions must be administered slowly to avoid rapid correction, which can result in central pontine myelinolysis. In patients who tolerate oral intake, fluid can be replaced orally, often with salt tablet supplements. Restriction of fluids is contraindicated in patients with CSW. If fluids are restricted, patients will be at risk for cerebral vasospasm, cerebral ischemia, and/or infarction.
Screening recommendations
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Screening for neuroendocrine dysfunction in mild TBI (mTBI) remains controversial because the exact prevalence is unknown. Screening should be considered for more complicated cases.
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Posttraumatic hypopituitarism happens frequently in the moderate to severe TBI population. Therefore, it’s suggested that all patients with moderate to severe TBI should have a hormonal assessment screening in the postacute phase, usually at 3 to 6 months post TBI or by 12 months at the latest. Logistically, this may be challenging, and often clinicians defer to a more pragmatic approach of screening those with clinical symptomatology of hypopituitarism.
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Early acute care screening for pituitary dysfunction is not recommended for the purpose of detecting post-TBI hypopituitarism. There is also no evidence that replacement of pituitary hormones in the acute phase is beneficial, and therefore it is not recommended except in rare cases.
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Consensus guidelines suggest that for individuals in a permanent vegetative state or at an extremely low level of functioning, the evaluation and treatment should be limited to hypoadrenalism, DI, SIADH, and thyroid dysfunction.
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Prospective studies examining pituitary dysfunction after TBI have demonstrated that hormonal dysfunction is often transient and usually recovers within 3 to 12 months of injury.
Treatment
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Many studies have shown that some neuroendocrine deficits may be transient and that there is no reliable way to predict the future of hormonal integrity after injury. However, PTH is felt to be permanent at 12 months.
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All patients 6 to 12 months postinjury should undergo immediate replacement of all pituitary deficiencies except for GH deficiency. GH deficiency may occur only in response to other hormonal deficiencies, so other hormonal replacements should be done before treating GH deficiency to avoid unnecessary expense.
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Gonadotrophin deficiencies may occur as a result of stress-induced impairment; because it is not a clinical emergency, the recommendation is to retest before initiation of hormonal replacement.
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If significant hormonal abnormalities are suspected, referral to endocrinology is indicated for dynamic testing and treatment.
Summary
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Growth hormone is the most common hormonal deficiency post TBI.
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Hormonal abnormalities in the acute setting are often transient;; therefore, screening should occur in the postacute setting unless clinically indicated.
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Hyponatremia is the most common electrolyte abnormality after neurologic injuries and is very common after TBI.
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The presence of diabetes insipidus early in the acute care stay is associated with increased mortality.
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PTH can occur in mTBI, but currently there are no guidelines or recommendations regarding screening in the mild TBI population, and it should only be done if the patient is symptomatic.
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There remains some controversy about the appropriate time for screening for PTH and treatment, but if any clinical suspicion exists, the patient should be screened and treated. The appropriate timing for screening and treatment for PTH remains controversial, but should take place if there is clinical suspicion of dysfunction.
Review questions
- 1.
A 59-year-old woman was admitted to your inpatient service, and you have noticed that on the second day of admission, she is lethargic and confused on morning rounds. Initial laboratory studies from admission have returned and show serum sodium of 124 mEq/L, serum osmolality of 230 mOsm/kg, and urine osmolality of 285 mOsm/kg. Nurses report low urine output but are unsure of how much she drank overnight. What is the most likely diagnosis?
- a.
Syndrome of inappropriate antidiuretic hormone (SIADH)
- b.
Diabetes insipidus
- c.
Cerebral salt wasting (CSW) syndrome
- d.
Psychogenic polydipsia
- a.
- 2.
You are seeing a patient who sustained a moderate traumatic brain injury (TBI) in a motor vehicle crash 6 months ago for a follow-up visit in your outpatient office to review laboratory studies. At the last appointment, your patient reported fatigue, hair loss, and weight gain. You obtained laboratory studies including thyroid function tests. What laboratory studies would support your hypothesis of hypothyroidism?
- a.
High thyroid-stimulating hormone (TSH) and high free T4
- b.
Low TSH and high free T4
- c.
High TSH and low free T4
- d.
Low TSH and high free T3
- a.
- 3.
You are giving a lecture on pituitary dysfunction after TBI to physical medicine and rehabilitation residents, and one of them asks what’s the most common hormonal abnormality after traumatic brain injury. You reply
- a.
thyroid hormone deficiency.
- b.
gonadotropin deficiency.
- c.
hyponatremia.
- d.
growth hormone deficiency.
- a.
Answers on page 392.
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Available on ExpertConsult.com
- 4.
You are seeing college athletes in your concussion clinic who are being sent by the athletic trainer for a presumed new concussion. A patient asks if she should undergo hormonal/pituitary gland screening because this is her second concussion in 5 years. She denies any symptoms such as fatigue, headache, weight changes, or mood changes. Your response is:
- a.
Yes.
- b.
No.
- c.
Let’s wait 3 months and see if these symptoms arise, then test.
- a.
- 5.
When should initial screening be done in a patient with severe TBI and suspected hypopituitarism?
- a.
On admission to acute care
- b.
1 to 2 months
- c.
3 to 6 months
- d.
1 year
- a.
- 6.
The unique anatomy of the pituitary makes it especially susceptible to which type of injury?
- a.
Direct traumatic injury
- b.
Edema
- c.
Ischemia/hypoxia
- d.
All of the above
- a.
- 7.
Pituitary injury has been found in which percentage of patients who died after severe TBI?
- a.
0%
- b.
33%
- c.
66%
- d.
100%
- a.
References
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