Mitchell E. Geffner, MD

Disclosures

Cancer Control. 2002;9(3) 

In This Article

Diagnosis of Hypopituitarism

The final diagnosis of GH deficiency must integrate clinical, auxological (growth), and biochemical data.[19] GH deficiency should be suspected if a child has reduced height velocity along with a delayed bone age, and low serum levels of the GH surrogates, insulin-like growth factor-1 (IGF-1), and insulin-like binding protein-3 (IGFBP-3) not otherwise explained by young age and/or undernutrition. The next step is then to measure serum GH levels. Unfortunately, beyond the first month of life, measurement of GH levels in a random blood sample is without value (to secure a diagnosis of GH deficiency) because most of the body's GH is made during sleep, with several significant peaks linked to deep (stage III-IV EEG) sleep, the first cycle of which usually occurs at approximately 60 to 90 minutes after falling sleep. Random GH measurements during the day, even in tall individuals, are frequently low and thus potentially misleading.

If most or all of these criteria are met, GH testing is then recommended by any of several physiologic or pharmacologic methods. The most commonly employed physiologic stimulus is exercise, but this is often difficult to standardize. Overnight serial blood sampling every 20 to 30 minutes was common in the early 1990s but lost favor because of inconvenience, cost, and lack of reproducibility.

A more common approach is stimulation testing (also referred to as provocative testing) with medications known to activate the physiologic regulation of GH secretion, notably the -adrenergic pathway (eg, clonidine[20] at the following dosages according to body weight: 50 µg for body weight 5 to 15 kg, 75 µg for 15.1 to 20 kg, 100 µg for 20.1 to 25 kg, 150 µg for 25.1 to 35 kg, 200 µg for 35.1 to 50 kg, and 250 µg for more than 50 kg).

Blood samples are procured 60 and 90 minutes after the clonidine is taken. Clonidine may cause sleepiness and a mild fall in blood pressure, but these effects are transient and usually resolve within 90 minutes. To mimic the other physiologic pathway of GH regulation involving the dopaminergic system, L-dopa combined with Inderal (propranolol) has been used, but L-dopa was recently taken off the market. These and all other stimulation tests must be performed in the fasting state (and, hence, early in the morning), as glucose intake suppresses GH secretion. GH provocation tests can also be performed using glucagon (0.1 mg/kg, maximum dose 1 mg)[21] or insulin (0.05 to 0.1 units of regular insulin per kilogram, depending on the index of suspicion), the latter known as an insulin tolerance test (ITT).[22] In both cases, hypoglycemia is induced. In the case of glucagon, blood sugar initially rises followed by stimulation of endogenous insulin leading to late hypoglycemia. For a hypoglycemic stimulus to be deemed adequate to stimulate GH, the plasma glucose concentration needs to fall by at least 50% from baseline. In the glucagon test, blood sampling is performed every 15 minutes for 1 hour and then every 30 minutes for the next 2 hours out to 180 minutes. For the ITT, blood sampling is performed every 15 minutes for 1 hour and then again 30 minutes later, with bedside and laboratory glucose testing, along with GH measurements at all time points and cortisol measurements at 0, 60, and 90 minutes. To obtain these multiple blood samples, a heparin lock should be placed in a large-bore vein at the start of the study. Glucagon or hypoglycemia itself may cause nausea and vomiting. Hypoglycemia results in uncomfortable adrenergic manifestations such as sweatiness, excessive hunger, and shakiness, and may also cause neuroglycopenic manifestations such as loss of consciousness or seizures. These tests can also be used to assess cortisol production, thus eliminating the need for an additional stimulation test either on the same day or on a different day. As such, these tests are moderately dangerous and need to be performed by experienced personnel in a hospital outpatient unit with resuscitative equipment and expertise as well as with a physician in attendance throughout the test. If dangerous hypoglycemia associated with diminished mental status occurs, 2 mL/kg of 25% dextrose should be immediately administered intravenously. The test will still be valid because the hypoglycemic stimulus was delivered so all blood samples should continue to be collected.

Arginine is another GH secretagogue that requires a 45-minute intravenous infusion (5 mL/kg of 10% arginine hydrochloride).[22] Arginine is an amino acid that is a non-specific stimulator of multiple hormones including insulin and glucagon, in addition to GH. There are no side effects with its use. Lastly, intravenous GHRH (at a dose of 1 µg/kg body weight) may be employed with sampling at 0, 5, 30, 45, 60, 90, and 120 minutes.[23] Its only frequent side effects are local injection site reactions.

GH deficiency is traditionally defined by all GH levels on all tests being less than 10 ng/mL as measured by traditional double-antibody radioimmunoassay. In certain clinical situations, such as known surgical transection of the hypothalamic-pituitary stalk or the administration of high-dose radiation to the hypothalamic-pituitary region, less rigorous GH testing is required.

Of note, the blood of children with untreated panhypopituitarism is mildly acidotic secondary to the absence of GH and its ability to regulate acid-base metabolism by the kidney.[24] Its presence is detected by finding a slightly low serum bicarbonate level that corrects completely with GH replacement.

The diagnosis of central hypothyroidism due to TSH deficiency requires low levels of free and/or total thyroxine (T4) in serum. On occasion, the free T4 level is at the low end of the normal range. A TSH level generally is not helpful. With pituitary failure, the TSH level would obviously be low or not measurable. Surprisingly, if the problem arises in the hypothalamus, the TSH is usually in the normal range or occasionally even slightly elevated for uncertain reasons. In some situations, administration of synthetic TRH, the hypothalamic factor that controls pituitary TSH secretion, may be necessary. This test can help distinguish whether the deficiency lies at the level of the pituitary (in which case the TSH level is very low and fails to increase) or at the hypothalamus (in which case the TSH level rises excessively and stays elevated for a longer period of time than occurs normally).[25]

The diagnosis of LH and FSH deficiencies in childhood can be the most problematic of all the pituitary hormones as throughout most of the first 10 years of life the serum concentrations of children are naturally low. Because LH and FSH levels are slightly higher in the first 6 months of life and then increase significantly after 10 years of age, random testing at these ages may indicate low levels.[26] Such testing is most informative when, in the teenager, there is also a failure to show clinical pubertal changes by age 13 years in girls (lack of breast development, sexual hair, and menses) and by age 14 years in boys (lack of testicular enlargement, penile growth, and sexual hair). In females, radiological confirmation of lack of pubertal initiation by pelvic ultrasound may be helpful if the ovaries and uterus are prepubertal in size.

As stated previously, cortisol deficiency is the most important parameter to consider in view of its role in regulating vital functions during stressful situations. Using random blood testing for this diagnosis requires an understanding of both the age-related changes (lower levels in younger than in older children) and "diurnal" changes (by time of day) in cortisol levels.[27] More specifically, in older children and adults, the highest cortisol levels are found at 8:00 AM. Thus, a low 8:00 AM serum cortisol level (less than 3 µg/dL in children between the ages of 1 and 16 years) would suggest deficiency. An indirect clue to the presence of cortisol deficiency is an increased percentage of eosinophils on a peripheral blood smear. As mentioned previously, more rigorous testing can be accomplished as part of the glucagon or insulin hypoglycemia GH tests or after administration of metyrapone, CRH, or low-dose synthetic ACTH, drugs that stimulate the adrenal glands to produce more cortisol if they can. The use of ACTH provocation may occasionally give a misleading picture of adequate adrenal reserve as sufficient cortisol may be produced in response to exogenous ACTH stimulation but is not produced under daily living conditions.

Prolactin excess is present if there is an elevated prolactin concentration in a random blood sample.

ADH deficiency or central DI is suspected if urination and thirst are excessive, and it is strongly suggested by the presence of increased levels of serum sodium along with dilute urine. If the diagnosis remains unclear, a water deprivation test can firmly prove or disprove this diagnosis.[28] This test involves fasting by the child (no food or liquids) for up to 8 hours and observing the child's urine output. A normal child will reduce urine output to avoid dehydration since there is no fluid intake. Under the same circumstances, a child with DI will continue to urinate and, if not monitored carefully, could become dehydrated and develop an elevated serum sodium concentration. Specific mathematical criteria that are derived from blood and urine test results during the water deprivation test are used to make the diagnosis of DI. This test should always be done under close medical supervision in either an experienced outpatient procedure unit or an inpatient setting.

Once the diagnosis of hypopituitarism has been made by appropriate hormonal testing, a head MRI scan (with gadolinium contrast) must be performed to look for a possible organic or structural basis. Nonserious abnormalities that can be associated with hypopituitarism include a small pituitary gland (for age) with filling of the sella with cerebrospinal fluid (empty sella) (Fig 3A) and an ectopic posterior pituitary gland. A midline syndrome is suggested by the absence of the septum pellucidum and/ or the corpus callosum. The most critical reason for obtaining the MRI scan is to detect a brain tumor in the hypothalamic-pituitary area, the most common of which is a craniopharyngioma. Radiological evidence of craniopharyngiomas can be seen on a lateral skull-ray in 89% of cases, which makes this an important screening test when this diagnosis is suspected in a child[29] (Fig 3B). Findings include erosion of the normal sellar architecture and/or the presence of suprasellar calcification. On MRI scans, the tumor usually contains a mixture of solid and cystic components (Fig 3C) and may contain a ring of calcification around a cystic component (the latter best seen on a computed tomographic scan) (Fig 3D). Other abnormalities that can be seen on the MRI scan include a transected stalk, small optic nerves, hydrocephalus, and vascular abnormalities.

Figure 3.

(A) Sagittal head MRI showing compressed pituitary contents (small arrow) with filling of sella turcica by cerebrospinal fluid (empty sella) (large arrow). (B) Lateral skull radiograph showing erosion of sella turcica (large arrow) and suprasellar calcification (small arrow) caused by a craniopharyngioma. (C) Coronal head MRI showing a craniopharyngioma in the suprasellar region containing a large cyst (small arrow) within a contrast-enhanced thin shell, along with mild hydrocephalus (large arrow). (D) Head CT scan showing contrast-enhanced ring of calcification around a craniopharyngioma and internal calcification (arrow).

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