Growth hormone deficiency laboratory findings

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Overview

An immediate investigation should be started in severe short stature defined as a short child more than 3 sd below the mean of children at the same age. Measurement of a random serum GH level alone is not helpful. Measurement of Insulin-like growth factor I (IGF-I) and Insulin-like growth factor binding protein-3 (IGFBP-3) is more helpful than GH level alone. GH stimulation tests are indicated for most patients suspected to have GHD. If the clinical and other laboratory criteria are sufficient to make the diagnosis of GHD, there is no need to perform the test. Pharmacologic stimuli include clonidine, glucagon, arginine, and insulin-induced hypoglycemia. Administration of sex steroids for a few days prior to the provocative GH testing reduces the chance of a false-positive result.

Laboratory Findings

Neonatal evaluation

• A GH level should always be measured:
  • In the presence of neonatal hypoglycemia
  • In the absence of a metabolic disorder.
  • A random GH measurement in a polyclonal RIA of less than 20 mg/L would suggest GHD in the newborn.
  • An IGFBP-3 measurement is of value for the diagnosis of GHD in infancy.

Children evaluation

Criteria to initiate immediate investigation include:

• Severe short stature, defined as a short child more than 3 sd below the mean of children at the same age
• Height more than 1.5 sd below the mid-parental height
• Height more than 2 sd below the mean and a height velocity over 1 year more than 1 sd below the mean for chronological age, or a decrease in height sd of more than 0.5 over 1 year in children over 2 yr of age;
• In the absence of short stature, a height velocity more than 2 sd below the mean over 1 yr or more than 1.5 sd sustained over 2 yr; this may occur in GHD, presenting in infancy, or inorganic GHD.
• Signs indicative of an intracranial lesion

The evaluation for GHD in a short child should not be initiated until other causes of growth failure, such as hypothyroidism, chronic systemic disease, Turner syndrome have been considered excluded.

Adults evaluation

Criteria to initiate immediate investigation include:

• Adults with known hypothalamic or pituitary disease:
  • Panhypopituitarism is documented deficiencies of thyroid-stimulating hormone (TSH), corticotropin (ACTH), and gonadotropins.
  • Multiple deficiencies of other pituitary hormones correlated highly with a subnormal GH response to a stimulation test.
  • A low serum IGF-1 concentration confirms the diagnosis of GH deficiency in these patients; provocative testing is not required.
• Adults with a history of GH deficiency in childhood. Some will be found to have normal GH secretion as adults, although this is not likely in those with GH deficiency due to an organic such as pituitary adenoma

What to measure?

GH secretion is pulsatile and its secretion is regulated by two hypothalamic factors; growth hormone-releasing hormone and somatostatin.

So, measurement of a random serum GH level alone is not helpful and usually other tests used with it:

• Insulin-like growth factor I (IGF-I)
• Insulin-like growth factor binding protein-3 (IGFBP-3) levels: it is the major serum carrier protein for IGF-I and the most GH dependent.

• Their concentrations often reflect the concentration of secreted GH.They are better tests than GH level because they are stable during the day and not pulsatile.

Limitations

• Serum IGF-I levels may be low in conditions other than GHD such as growth hormone insensitivity, hypothyroidism, renal failure, diabetes, and cancer.

Interpretation

• Reduced level of IGF-I and IGFBP-3 with delayed bone age: provocative GH testing is needed. If the growth failure is severe and IGF-I and IGFBP-3 are severely low, there is no need to perform GH stimulation testing.

• Normal IGF-1 and IGFBP-3: no further testing is required.

GH stimulation tests

• It is indicated for most patients suspected to have GHD.
• The results should be interpreted in the context of bone age, and IGF-1 and IGFBP-3 concentrations.

• If the clinical and other laboratory criteria are sufficient to make the diagnosis of GHD, there is no need to perform the test. 

• A serum GH concentration of >10 mcg/L, but a cutoff of 7.5 mcg/L is often used for modern assays.

• The stimulation tests are performed after an overnight fast. Serum samples are collected at intervals to capture the peak GH level.

• Two different stimuli should be used for most patients.
• In a patient with other pituitary hormone defects or a genetic defect, one test is sufficient to establish the diagnosis.
• Pharmacologic stimuli include clonidine, glucagon, arginine, and insulin-induced hypoglycemia:

Test	Mechanism	Dose	Peak of effect	Side effect
Clonidine	stimulation of GHRH via alpha-adrenergic pathways	5 mcg/kg	One hour	Hypotension and hypoglycemia
Arginine	Stimulates GH release	0.5 g/kg	One hour	No side effects
Glucagon	Transient hyperglycemia	0.03 mg/kg	Three hours	Nausea, vomiting, sweating, and headache
Insulin	Insulin-induced hypoglycemia is a potent stimulant of GH release			Hypoglycemia

Interpretation

• The interpretation of the test results depends upon age and sex hormone concentrations.
• Children with constitutional delay of growth and puberty may have low GH results on provocative testing in the absence of true GHD.
• Administration of sex steroids for a few days prior to the provocative GH testing reduces the chance of a false-positive result.