What is the diagnostic approach for growth hormone deficiency?

Diagnostic Approach for Growth Hormone Deficiency

Clinical Context: Who to Test

Only evaluate patients with specific risk factors for pituitary dysfunction—do not screen the general population. 1, 2

Test for GHD in patients with:

• Sellar masses or pituitary tumors (including adenomas, craniopharyngiomas) 1
• History of pituitary surgery or cranial irradiation 1, 2
• Traumatic brain injury or subarachnoid hemorrhage 1, 2
• Childhood-onset GHD transitioning to adulthood 1, 3
• Multiple other pituitary hormone deficiencies (≥3 deficiencies strongly suggest GHD) 4, 2

In children specifically, evaluate those with:

• Diminished height velocity and short stature 5
• Delayed bone age relative to chronological age 6
• Clinical signs of hypothalamic-pituitary dysfunction 7

Pre-Testing Requirements

Before testing for GHD, replace all other pituitary hormone deficiencies first. 1, 2 This is critical because:

• Untreated hypothyroidism and adrenal insufficiency can falsely suppress GH responses 1
• Glucocorticoid and thyroid replacement must be optimized before interpreting GH testing 4

Diagnostic Algorithm

Step 1: Measure IGF-1 (Initial Screening)

Obtain a single serum IGF-1 level using age- and sex-specific reference ranges. 1, 2

• A low IGF-1 plus ≥3 other pituitary hormone deficiencies is sufficient to diagnose GHD without provocative testing 4, 2
• IGF-1 alone lacks sensitivity and specificity, so normal levels do not exclude GHD 1, 5
• Do not use random GH measurements—GH secretion is pulsatile and random levels are not interpretable (except in neonates) 1, 5

Step 2: GH Provocative Testing (When Required)

If IGF-1 is low but <3 pituitary deficiencies exist, or if IGF-1 is normal but clinical suspicion remains high, perform GH stimulation testing. 1, 2

Commonly used provocative tests include: 1, 2, 5

• Insulin tolerance test (ITT) – considered gold standard but carries hypoglycemia risk
• Glucagon stimulation test – safer alternative to ITT
• GHRH + arginine test
• GHRH + GH-releasing hexapeptide test
• Macimorelin test – newer oral option

Critical caveats for interpreting stimulation tests: 3, 5

• Peak GH cutoffs vary by test, age, sex, and BMI – no universal standard exists
• In children: cutoff typically <10 μg/L, but this threshold has evolved over time 6
• In adults: cutoffs differ across tests and are influenced by body composition 2, 5
• Pubertal status affects results in children – consider sex steroid priming in prepubertal adolescents, though no consensus exists on this practice 3
• Nutritional status impacts testing – malnutrition can suppress GH responses 3
• GH assay heterogeneity – results vary between laboratories and assay methods 3, 2

Step 3: Pituitary MRI

Obtain pituitary MRI with contrast in all patients being evaluated for GHD. 7, 3, 6

• MRI findings provide both diagnostic and prognostic information 3
• Look for structural abnormalities: pituitary hypoplasia, ectopic posterior pituitary, stalk interruption, masses 6
• Normal MRI does not exclude GHD but reduces likelihood 3

Step 4: Bone Age Assessment (Pediatric Patients)

Perform left wrist radiograph to assess skeletal maturation. 4, 6

• Delayed bone age supports GHD diagnosis and indicates remaining growth potential 4
• Bone age assessment helps predict adult height and guides treatment timing 8

Step 5: Genetic Testing (Selected Cases)

Consider genetic testing when: 3, 6

• Multiple pituitary hormone deficiencies are present
• Family history suggests inherited disorder
• Syndromic features are present
• Congenital structural abnormalities are seen on MRI

Common genetic causes include mutations in GH1, GHRHR, PROP1, POU1F1, and others 3, 6

Special Populations

Transitional Age (Childhood to Adult)

Retest all patients with childhood-onset GHD after completion of linear growth to determine if GHD persists into adulthood. 3

• Approximately 30-50% of childhood GHD resolves after growth completion 3
• Retesting should occur at least 1 month after stopping GH therapy 3

Post-Cushing Disease Remission

Test for GHD soon (within 3 months) after definitive therapy in children who have not completed growth. 7

• GH deficiency is common after transsphenoidal surgery and radiotherapy 7
• Early detection and treatment are critical given the limited window for catch-up growth 7, 9

Common Pitfalls to Avoid

• Do not rely on a single IGF-1 measurement to exclude GHD – sensitivity is insufficient 1
• Do not perform GH testing without first optimizing other hormone replacements – results will be unreliable 1, 2
• Do not use the same GH cutoff across all provocative tests – each test has specific diagnostic thresholds 2, 5
• Do not delay evaluation in children with growth velocity <7 cm/year – this warrants immediate investigation 8
• Do not assume normal laboratory values for other hormones mean GH therapy is unnecessary – GHD is a separate entity requiring independent assessment 4