Growth Hormone Deficiency

Primary Author Meikle, A. Wayne, MD.

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.

Current Stimulation Testing Guidelines

Stimulation TestRecommendationsLimitations
Insulin tolerance test (ITT) – evaluates the integrity of the hypothalamic-pituitary axis and simulates adrenocorticotrophin
  • Recommended test; has sufficient sensitivity and specificity (The Endocrine Society 2011; Growth Hormone Research Society 2007)
  • GH <4 ng/mL is diagnostic
  • Requires constant monitoring of patient
  • Not indicated in patients with  severe seizure disorders or ischemic heart disease and in the elderly
  • Several studies question reproducibility and specificity
Arginine stimulation with growth hormone-releasing hormone (GHRH) – evaluates maximal secretory capacity; stimulates both hypothalamus and pituitary
  • Recommended test; has sufficient sensitivity and specificity (The Endocrine Society 2011; Growth Hormone Research Society 2007)
  • 0.5 g/kg body weight IV arginine plus GHRH given over 30 minutes with serum GH at 0, 30, 60, 90 minutes
    • Normal GH – >5 ng/mL in adults
    • Positive GH – <3 ng/mL
  • Not affected by age
  • Currently, not available in the U.S.
  • Not useful if recent (<10 years) hypothalamic etiology (eg, irradiation) for GH deficiency; results may be misleading (false-normal result)
  • GH deficiency due to hypothalamic disease may be missed
GHRH plus growth hormone-releasing peptide (GHRP) – evaluates maximal secretory capacity; stimulates both hypothalamus and pituitary
  • Recommended test; has sufficient sensitivity and specificity (Growth Hormone Research Society 2007; not addressed by Endocrine Society)
  • Preferred alternative to ITT since GHRH is not available in U.S.
  • GH deficiency due to hypothalamic disease may be missed
Glucagon stimulation test (GST) – mechanism by which glucagon stimulates GH secretin is unknown
  • Recommended when GHRH not available and ITT contraindicated or not practical (The Endocrine Society 2011)
  • Suitable alternative when GHRH or GHRP not available and ITT contraindicated (Growth Hormone Research Society 2007)
  • Not indicated in patients with malnutrition, pheochromocytome, or insulinoma
  • Performance on diabetics patients unknown

Additional Notes

  • Stimulation tests
    • One stimulation test is sufficient for diagnosing GH deficiency in adults
    • Optional when >3 deficiencies in pituitary axis hormones are present and growth hormone levels are low (ie, IGF-1 levels below reference range)
    • Only patients with high pretest probability should undergo testing; stimulation tests have high false-positive rates
  • Results that are diagnostic of GH deficiency
    • A low IGF-1 and a low GH stimulation response
    • Severely low concentrations of IGF-1
  • Results that are suggestive of GH deficiency
    • IGF-1 (low), IGFBP-3 (low)
  • Results of all tests are affected by obesity
  • Deficiencies in other anterior pituitary hormones can occur with low IGF-1 –  consider testing for LH/FSH, TSH, ACTH
References:  Ho KK 2007; Kargi A 2012; Molitch ME et al 2011; Stanley T 2012

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

  • Linear height velocity usually accelerates with GH replacement
    • May not occur in idiopathic short stature (ISS)
  • Repeat GH testing – only necessary after puberty to assess need for lifelong GH supplementation   

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

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

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
Test Name and Number Recommended Use Limitations Follow Up
Growth Hormone 0070080
Method: Quantitative Chemiluminescent Immunoassay

Initial test for GH deficiency

Low or normal value does not rule out GH deficiency

 
IGF-1 (Insulin-Like Growth Factor 1) 0070125
Method: Quantitative Chemiluminescent Immunoassay

Concurrent test for GH deficiency

Normal value does not rule out GH deficiency May be used in conjunction with IGFBP-3
IGF Binding Protein-3 0070060
Method: Quantitative Chemiluminescent Immunoassay

May be used to assess GH deficiency

Normal value does not rule out GH deficiency

May be used in conjunction with IGF-1
Growth Hormone, 0 Minutes 0070081
Method: Quantitative Chemiluminescent Immunoassay

GH stimulation testing, sample 1

Insulin tolerance test or arginine stimulation test with growth hormone releasing hormone is preferred testing

   
Growth Hormone, 30 Minutes 0070082
Method: Quantitative Chemiluminescent Immunoassay

GH stimulation testing, sample 2

   
Growth Hormone, 60 Minutes 0070083
Method: Quantitative Chemiluminescent Immunoassay

GH stimulation testing, sample 3

   
Growth Hormone, 90 Minutes 0070084
Method: Quantitative Chemiluminescent Immunoassay

GH stimulation testing, sample 4

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
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