What are the recommended methods for measuring and testing growth hormone (GH) in suspected GH deficiency?

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Growth Hormone Testing in Suspected GH Deficiency

The insulin tolerance test (ITT) and GHRH-arginine test are the recommended first-line provocative tests for diagnosing adult GH deficiency, with diagnostic GH cut-offs of <5.1 µg/L and <4.1 µg/L respectively, though when GHRH is unavailable, the glucagon stimulation test serves as an acceptable alternative. 1

Clinical Context Determines Testing Strategy

Before ordering any provocative test, ensure adequate replacement of other deficient pituitary hormones, as this affects test accuracy 1. The approach differs based on clinical presentation:

Patients Who May NOT Need Provocative Testing

In adults with childhood-onset GHD who have structural lesions, multiple pituitary hormone deficiencies (≥3 additional deficiencies), or proven genetic causes, a low IGF-I level measured at least 1 month off GH therapy is sufficient to confirm persistent GHD without additional stimulation testing. 1

Similarly, adults with hypothalamic-pituitary disease but preserved pituitary function and IGF-I SDS ≥0 have a probability of GHD below 20%, making stimulation testing potentially unnecessary in this subgroup 2.

Patients Who Require One vs. Two Tests

The number of tests needed depends on the presence of other pituitary hormone deficiencies 3:

  • Patients with 2-3 additional pituitary hormone deficiencies: One provocative test is sufficient, as concordance between tests exceeds 83% 3
  • Patients with isolated suspected GHD or only 1 additional deficiency: Two different provocative tests are required due to higher misclassification rates (23-33% discordance) 1, 3

This distinction exists because the difference between GH responses to different stimuli increases in patients with milder GHD, leading to potential misclassification with single testing 3.

Recommended Provocative Tests (In Order of Preference)

First-Line Tests

1. Insulin Tolerance Test (ITT)

  • Diagnostic cut-off: Peak GH <5.1 µg/L (96% sensitivity, 92% specificity) 4
  • Considered the reference standard 1
  • Contraindications: Seizure disorders, ischemic heart disease, severe hypopituitarism 1

2. GHRH-Arginine Test

  • Diagnostic cut-off: Peak GH <4.1 µg/L (95% sensitivity, 91% specificity) 4
  • Performs nearly as well as ITT with better tolerability 1
  • Critical caveat: Can give falsely normal results in hypothalamic GHD (e.g., post-irradiation within 10 years) because GHRH directly stimulates the pituitary 1
  • Current limitation: GHRH has been commercially unavailable in the US since 2008 1

Alternative When GHRH Unavailable

3. Glucagon Stimulation Test

  • Diagnostic cut-off: Peak GH <2.5-3.0 µg/L 1
  • Monitor GH over at least 3 hours (delayed response compared to other tests) 1
  • Important safety measure: Monitor glucose for delayed hypoglycemia 1
  • Obesity blunts response 1

Less Reliable Tests (Use Only If Above Unavailable)

4. Arginine + L-DOPA: Cut-off <1.5 µg/L for 95% sensitivity 4

5. Arginine alone: Cut-off <1.4 µg/L for 95% sensitivity 4

6. L-DOPA alone: Cannot achieve 95% specificity; not recommended 4

Role of IGF-I Measurement

IGF-I alone cannot diagnose GHD in most cases, but provides important supporting information 1, 5:

  • Normal IGF-I does NOT exclude severe GHD - provocative testing still required 5
  • Very low IGF-I (<77.2 µg/L) in high-suspicion patients (multiple pituitary deficiencies, structural lesions) strongly supports GHD and may suffice for diagnosis 1, 4
  • IGF-I interpretation requires consideration of age, sex, nutritional status, liver disease, diabetes control, and oral estrogen use 1

Critical Caveats for Test Interpretation

Body Mass Index Effects

Obesity significantly blunts GH responses to all provocative tests 5. Cut-off values should be adjusted for BMI categories to avoid:

  • False-positive diagnosis in obese patients
  • False-negative diagnosis in lean patients 5

The GHRH-arginine test particularly requires BMI-adjusted cut-points 1.

Assay Variability

GH and IGF-I assays show considerable between-method variability 6. Clinicians must understand the specifications and limitations of their laboratory's specific assay, as this affects diagnostic accuracy and treatment monitoring 6.

Test Reproducibility

The magnitude of difference between GH responses to different tests increases with higher underlying mean GH values (correlation 0.88, p<0.0001), meaning patients with milder GHD show greater test-to-test variability 3.

Practical Testing Algorithm

  1. Assess clinical context: Number of other pituitary deficiencies, structural lesions, genetic causes
  2. Measure IGF-I: If very low with high clinical suspicion and ≥3 pituitary deficiencies, diagnosis confirmed
  3. If provocative testing needed:
    • First choice: ITT (if no contraindications) or GHRH-arginine (if available and no recent hypothalamic pathology)
    • Second choice: Glucagon test (monitor 3+ hours, watch for hypoglycemia)
  4. Number of tests: Two tests if isolated GHD or 1 additional deficiency; one test if ≥2 additional deficiencies
  5. Apply test-specific cut-offs and adjust for BMI where validated

References

4
Research

Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency.

The Journal of clinical endocrinology and metabolism, 2002

5
Research

Diagnosis of adult GH deficiency.

Pituitary, 2008

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