Growth Hormone Deficiency

Key Points

Growth Hormone Deficiency Stimulation Testing in Adults

Growth hormone (GH) deficiency leads to reduced quality of life and the development of significant comorbid illnesses. The diagnosis of deficiency is difficult because GH is secreted in a pulsatile fashion; a random low GH test is nondiagnostic. Insulin-like growth factor 1 (IGF-1) has a longer half-life than GH, but the values for normal and deficiency overlap enough to make the IGF-1 test nondiagnostic. Therefore, diagnosis of growth hormone deficiency requires dynamic testing of the pituitary axis using stimulation testing. In light of the lack of availability of growth hormone-releasing hormone (GHRH) in the U.S., the insulin tolerance testing (ITT) is recommended or when ITT is contraindicated, glucagon stimulation testing has adequate sensitivity and specificity for diagnosing GH deficiency.

For current stimulation testing guidelines, see the table below.

Diagnosis

Indications for Testing

• Evidence of hypothalamic-pituitary disease
• Growth hormone (GH) deficiency in childhood
• Signs and symptoms of pituitary dysfunction in adulthood

Laboratory Testing

• Refer to  Key Points for guideline recommendations regarding laboratory testing for GH deficiency

Imaging Studies

• If no obvious etiology of deficiency, perform CT or MRI to rule out tumor

Monitoring

Clinical Background

Growth hormone (GH) deficiency is usually a condition acquired in adulthood but may also be found in children due to congenital factors.

Epidemiology

• Prevalence – uncommon

Etiology (Acquired)

• Acquired deficiency typically caused by damage to the pituitary; may also be caused by damage to hypothalamus (rare)
  • Pituitary damage – may be caused by surgery, tumor, granulomas, cranial irradiation, trauma, hypophysitis
    • Usually results in a sequential loss in anterior pituitary function
      • Loss of GH, follicle stimulating hormone (FSH), and leuteinizing hormone (LH)
      • May be followed by loss of thyroid stimulating hormone (TSH) and loss of adrenocorticotropic hormone (ACTH)
  • Hypothalamic damage – hypothalamic-releasing hormones help regulate certain pituitary hormones

Pathophysiology

• GH secreted by the anterior pituitary
  • Binds to transmembrane receptor with GH-binding protein
  • Leads to production of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3)
• GH secretes in pulsatile fashion – natural impetus for secretion is sleep
  • GH rises at night and sporadically during the day – may be related to meals
  • GH increases in response to hypoglycemia

Clinical Presentation

• Constitutional – fatigue, low self-esteem
• Increased body fat, reduced lean mass
• Reduced exercise capacity
• Dyslipidemia
• Complications – coronary artery disease, hypertension, insulin resistance, osteopenia

Treatment

• GH replacement

Pediatrics

Clinical Background

Epidemiology

• Prevalence – not uncommon
• Age – recognized by slow linear growth of <1 percentile
• Sex – M>F

Etiology (Congenital)

• Idiopathic growth hormone deficiency
• Inborn errors of the POU1F1 gene
• PROP1 mutations
• Growth hormone releasing hormone (GHRH) gene defects
  • Genetic insensitivity to GH

Clinical Presentation

• Short stature (defined as height >2 standard deviations below the mean), severe growth failure, delayed bone age

Treatment

• FDA indications for GH replacement
  • GH deficiency  
  • Other indications
    • Idiopathic short stature (ISS) – most controversial indication
    • Small for gestational age (SGA) infants
      • 90% SGA infants catch up in growth by age 2 and do not require GH supplementation
    • Chronic renal insufficiency
      • Causes in children
        • Structural – usually congenital
        • Metabolic – oxalosis, cystinosis
        • Acquired – infection
      • Renal disease onset at a young age leads to greater stature loss
        • Dialysis/transplant patients often do not normalize growth
    • Turner syndrome
    • Prader-Willi syndrome
    • Noonan Syndrome

Diagnosis

Indications for Testing

• Short stature (>2 standard deviations below mean), severe growth deceleration, history of brain tumor, cranial irradiation, radiologic evidence of pituitary abnormality
• Rule out all other causes of short stature
  • Hypothyroidism
  • Chromosomal disorders
    • Prader-Willi syndrome
    • Turner syndrome
  • Chronic systemic disease
    • Renal failure – most common
    • Malabsorption – celiac disease
  • Skeletal disorders
  • ISS

Laboratory Testing

• Initial serum GH concentrations cannot be used alone to diagnose deficiency due to pulsatile nature of GH release; perform insulin-like growth factor 1 (IGF-1) testing simultaneously
  • If GH concentrations remain low after stimulation, then GH deficiency confirmed
• Insulin tolerance test (ITT) – insulin-induced hypoglycemia (IGF-1 testing alone is insufficient to diagnose GH deficiency)
  • Method – 0.1 unit of insulin/kg of body weight and measure GH at 0, 15, 30, 60 and 90 minutes
• Growth hormone releasing hormone plus arginine – method of choice
  • Other agents include L-dopa, arginine, clonidine, and glucagon
  • GH >7 ng/mL – normal stimulation result in children
    • Some experts consider values of 5-8 ng/mL equivocal and only peak values >8 ng/mL as truly normal
• Results suggestive of GH deficiency following stimulation tests
  • IGF-1 or insulin growth factor binding protein 3 measurement – low

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
IGF Binding Protein 2 0098842 Method: Quantitative Radioimmunoassay
IGF Binding Protein-1 0098843 Method: Quantitative Radioimmunoassay	Used for research interest only Patient should fast overnight (12 hours) prior to collection
Growth Hormone Antibody 0092142 Method: Qualitative Radiobinding Assay
Growth Hormone, 15 Minutes 0070048 Method: Quantitative Chemiluminescent Immunoassay
Growth Hormone, 45 Minutes 0070049 Method: Quantitative Chemiluminescent Immunoassay
Growth Hormone, 120 Minutes 0070164 Method: Quantitative Chemiluminescent Immunoassay
Insulin, 30 Minutes 0070064 Method: Quantitative Chemiluminescent Immunoassay
Insulin, 60 Minutes 0070066 Method: Quantitative Chemiluminescent Immunoassay
Insulin, 120 Minutes 0070068 Method: Quantitative Chemiluminescent Immunoassay
Luteinizing Hormone and Follicle Stimulating Hormone 0070193 Method: Quantitative Electrochemiluminescent Immunoassay
Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108 Method: Quantitative Electrochemiluminescent Immunoassay
Thyroid Stimulating Hormone 0070145 Method: Quantitative Chemiluminescent Immunoassay
Adrenocorticotropic Hormone 0070010 Method: Quantitative Chemiluminescent Immunoassay