Panhypopituitarism Workup

Updated: Apr 27, 2017
  • Author: Robert P Hoffman, MD; Chief Editor: Sasigarn A Bowden, MD  more...
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Workup

Laboratory Studies

The diagnostic evaluation of a child with hypopituitarism is divided into 2 portions: recognition of the hormonal deficiencies and determination of the cause. Genetic testing is available at various commercial and academic laboratories for mutations associated with hypopituitarism.

Thyroid-stimulating hormone (TSH) deficiency

Hypothyroidism secondary to TSH deficiency is the easiest of the hormonal abnormalities to diagnose. Children have decreased free thyroxine (T4) levels and TSH levels that are within the reference range or low. Occasionally, a child with hypothalamic hypopituitarism may have a mildly elevated TSH level.

Test any child with TSH deficiency for adrenal function prior to T4 replacement. Correction of hypothyroidism without appropriate cortisol replacement can precipitate an adrenal crisis. This is most likely because of accelerated cortisol metabolism upon thyroid hormone treatment.

Adrenocorticotropic hormone (ACTH) deficiency

Testing for ACTH deficiency is more complex. The key element is not the basal cortisol level present but the response to stress.

In the past, the most frequently used test was the intravenous ACTH stimulation test. In this test, 250 mcg of ACTH 1-24 (Cortrosyn) is administered as an intravenous bolus with measurements of cortisol at 0 minutes, 30 minutes, and 60 minutes. This test has a high specificity. A peak cortisol level below 18 mcg/dL is suggestive of cortisol deficiency either because of ACTH deficiency or because of primary adrenal disease. The test has low sensitivity. Many patients with ACTH deficiency as determined by insulin tolerance test results have responses over 18 mcg/dL. Because of its ease of performance, it may be a reasonable first test but a result within the reference range should never be accepted as an indication of ACTH sufficiency. [23]

A low-dose 1-mcg ACTH stimulation test can be used to increase the specificity of the high-dose test. Results of the 1-mcg test correspond well with results from insulin-induced hypoglycemia. The low dose of ACTH does not stimulate cortisol production in an unprimed adrenal gland. However, care must be taken in diluting the ACTH to obtain the 1-mcg dose. [24]

The insulin tolerance test is much more sensitive and equally specific for ACTH deficiency but entails significant risks. Draw a baseline cortisol level and administer insulin (0.075-0.1 U/kg intravenously). Blood is obtained every 15 minutes for 1 hour to measure cortisol and glucose levels. For the test to be adequate, the plasma glucose level should decrease to less than 45 mg/dL. This usually happens at the 15-minute sample. The plasma cortisol level should increase to more than 18 mcg/dL, or at least double, in response to hypoglycemia. [23]  Obviously, this test involves significant risk to the patient. Therefore, intravenous access must be assured and trained personnel must be present to immediately treat a serious hypoglycemic reaction with intravenous dextrose if needed. Such treatment does not negate the results of the test, and blood sampling should continue until the completion of the study.

The glucagon stimulation test is one last convenient test that may be used. Glucagon, 0.1 mg/kg (maximum 1 mg), is administered intravenously or intramuscularly and blood is obtained every 30 minutes for 3 hours for glucose and cortisol levels. An increase in the plasma cortisol level should occur during the fall in plasma glucose levels over the last 1-2 hours of the test. [25]  This test is useful in neonates, in whom the adequacy of venous access is a concern, if dextrose must be administered during insulin-induced hypoglycemia. As in the insulin tolerance test, the cortisol response that occurs in the glucagon stimulation test depends on an increase in the patient's own ACTH secretion and is therefore useful in assessing the entire hypothalamic-pituitary-adrenal axis.

Single measurement of plasma dehydroepiandrosterone sulfate levels has been shown to be at least a reasonable screening test for ACTH deficiency with good sensitivity and sensitivity when compared with the insulin tolerance test. The disadvantage to this test is that normal levels are age dependent, and, thus, the laboratory must have age-matched control normal levels available. [26]

Gonadotropin deficiency

Gonadotropin deficiency is difficult to assess in girls prior to puberty or in boys after age 3-6 months and before puberty.

Males

Infant males aged 20-60 days have peak testosterone levels of 60-400 ng/dL. At this age, a level below this range with low luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels suggests gonadotropin deficiency.

At puberty, testosterone levels and LH levels in boys should increase, but the reference range testosterone level depends on the pubertal stage. A circadian variation is observed, with higher levels during the night. Suspect hypogonadotropism if a boy has not started puberty by age 16 years, starts puberty but does not progress to completion, or has completed puberty but has a testosterone level less than 300 ng/dL with low LH and FSH levels.

Females

Girls have minimal estradiol secretion during infancy, thus making the diagnosis of gonadotropin deficiency difficult at this age.

Estradiol levels vary throughout the menstrual cycle. Suspect gonadotropin deficiency in girls with no breast development by age 14 years, no periods by age 16 years, or secondary amenorrhea and low LH and FSH levels

Gonadotropin-releasing hormone (GNRH) testing

Testing with any one of numerous short-acting GnRH analogues may also be helpful. For leuprolide acetate, the dose is 20 mcg/kg, and samples are obtained to measure LH and FSH levels at baseline and at 2 hours, 4 hours, 6 hours, and 24 hours after the leuprolide. For males, baseline and 24-hour testosterone levels may also be helpful.

In healthy pubertal children, the LH response exceeds the FSH response. In prepubertal children, the FSH response exceeds the LH response. In patients with complete gonadotropin deficiency, little to no response of either LH or FSH occurs. An intermediate response does not distinguish the prepubertal child with gonadotropin deficiency from the child with simple delayed puberty. Hence, this test is of limited value. An increase in testosterone levels in males after 24 hours suggests an intact hypothalamic-pituitary-gonadal axis.

Inhibin B levels less than 35 pg/mL have recently been shown to have 100% specificity and sensitivity for hypogonadotropism in prepubertal boys aged 14-18 years. For patients with Tanner stage 2 genital development, measurement of inhibin B levels (< 65 pg/mL) also had good sensitivity and specificity for identification of isolated gonadotropin deficiency. For patients with other pituitary deficiencies, low testosterone (< 25 ng/dL) levels were the best diagnostic test. [27]

Growth hormone (GH) deficiency

The best method to diagnose a GH deficiency is controversial.

In the poorly growing child, low baseline measurements of insulinlike growth factor 1, insulinlike growth factor 2, and insulinlike growth factor–binding protein 3 suggest GH deficiency. GH levels less than 5 ng/dL at the time of spontaneous hypoglycemia also suggest GH deficiency. Beyond this, other stimulatory tests are used.

Most physicians perform a combination of 2 tests on children with suspected GH deficiency. Again, the criterion standard is insulin-induced hypoglycemia, as described for cortisol deficiency. Arginine infusion with 0.5 mg/kg over 30 minutes is probably equally efficacious. Beyond these 2 tests, other drugs used include glucagon, clonidine, and propranolol. [28]

The biggest controversy is likely establishing the cutoff point for diagnosis of GH deficiency. Over the past 20 years, a peak level less than 10 ng/dL measured by routine radioimmunoassay was considered diagnostic. Before that, a level of 7 ng/dL was used. Differences in radioimmunoassay techniques may alter reported GH levels. Recent studies question the reliability of any testing. A study of children without deficiencies demonstrated a lower 95% confidence interval of 1.9 ng/mL in prepubertal individuals not primed with sex steroids. [29] Sex steroid priming increased this to 7.2 ng/mL.

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Imaging Studies

Head MRI

Perform this test in all children with panhypopituitarism. Look for either underlying structural abnormalities or tumors that may be the cause of the hypopituitarism. [30]

The value of such imaging in children with an isolated pituitary hormonal deficiency is not clear. Perform imaging in such cases based on the clinical judgment of the physician.

Perform imaging in all patients with central diabetes insipidus because diabetes insipidus is frequently associated with an organic mass lesion.

Left hand and wrist radiography for bone age

This radiograph must be read by an experienced individual. The result can provide guidance regarding the patient's growth potential and sex hormone exposure.

Bone ages are frequently delayed in patients with hypopituitarism. The diagnostic sensitivity and specificity are low.

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