Growth Hormone Deficiency

Growth hormone deficiency (GHD) is the most common hormone deficiency associated with pituitary dysfunction, occurring in 61-100% of individuals with pituitary hormone deficiency. In adults, it is most commonly caused by pituitary damage from trauma, compression, or radiation therapy. GHD leads to the development of significant comorbid diseases and reduced quality of life. Once identified, it can be corrected with lifelong growth hormone (GH) replacement.

Diagnosis

Indications for Testing

  • Radiologic evidence of structural hypothalamic-pituitary disease
  • Signs and symptoms of pituitary dysfunction in adulthood
  • History of surgery or irradiation to hypothalamus or pituitary gland
  • History of traumatic brain injury or subarachnoid hemorrhage
  • Symptoms suggestive of GHD – loss of muscle mass, central adiposity, low bone density, fatigue, and insomnia

Laboratory Testing

Static Growth Hormone Testing
Test Uses Limitations

GH

Aid in diagnosis of GH excess or deficiency disorders

Single, random GH result is nondiagnostic because GH is produced in a pulsatile fashion

IGF-1

Concentrations are less variable than GH concentrations

Low IGF-1 concentration and GH stimulation response are diagnostic of GHD

Severely low IGF-1 concentration is diagnostic of GHD

Low concentration is suggestive of GHD, but insufficient to diagnose GHD, and may be secondary to uncontrolled diabetes, liver disease, or oral estrogen therapy

Normal concentration does not rule out GHD

IGFBP-3

May be used in addition to GH concentration and IGF-1 testing; concentrations reflect IGF-1 concentrations

Low concentration is suggestive of GHD, but insufficient to diagnose GHD

IGF-1, insulin-like growth factor 1; IGFBP-3, insulin-like growth factor binding protein 3

Sources: Ho, Growth Hormone Research Society, 2007; Kargi, 2012; Molitch, Endocrine Society, 2011; Stanley, 2012

  • Stimulation testing (see table below)
    • One positive stimulation test is sufficient for diagnosing GHD in adults
    • Optional when patient has deficiencies in three or more pituitary axis hormones and GH levels are low (eg, IGF-1 levels below reference range)
    • Only patients with high pretest probability for GHD should undergo testing; stimulation tests have high false-positive rates
Stimulation Testing
Test Uses Protocol Limitations

ITT

Recommended test; has sufficient sensitivity and specificity (ES, 2011; GRS, 2007)

Inject 0.1 units of insulin/kg of body weight; measure GH at baseline and at 15, 30, 60, and 90 minutes

GH <4 ng/mL is diagnostic

Requires constant monitoring

Not indicated in elderly patients (>60 yrs) or in patients with diabetes, severe seizure disorders, or ischemic heart disease

Several studies question reproducibility and specificity

Glucagon

Recommended when GHRH is not available and ITT is contraindicated or not practical (ES, 2011)

Suitable alternative when GHRH or GHRP is not available and ITT is contraindicated (GRS, 2007)

Inject 1 mg glucagon intramuscularly (1.5 mg for individuals >90 kg)

Measure plasma GH at 30, 60, 90, 120, and 180 minutes; alternatively, can measure at 220 and 240 minutes

Has less diagnostic value than ITT

Not indicated in patients with malnutrition, pheochromocytoma, or insulinoma

Performance in patients with diabetes is unknown

GHRH

Recommended test; has sufficient sensitivity and specificity (ES, 2011; GRS, 2007)

n/a

Currently unavailable in the U.S.

ES, Endocrine Society; GHRH, growth hormone-releasing hormone; GHRP, growth hormone-releasing hexapeptide; GRS, Growth Hormone Research Society; ITT, insulin tolerance test; n/a, not available

Sources: Ho, Growth Hormone Research Society, 2007; Kargi, 2012; Molitch, Endocrine Society, 2011; Stanley, 2012

Imaging Studies

  • If no obvious etiology of GHD
    • Magnetic resonance imaging (MRI) of head without contrast
    • Computed tomography (CT) of head – acceptable if MRI is contraindicated or not available

Monitoring

  • IGF-1 or IGFBP-3
    • Use for dose titration
    • Monitor patient every 1-2 months until an appropriate concentration is reached, then at 6-month intervals

Background

Epidemiology

Prevalence – rare in adults

Pathophysiology

  • GH is secreted by somatotropic cells of the anterior pituitary gland
    • Secretion is stimulated by GHRH released by hypothalamus
    • GH binds to transmembrane receptors on target cells with GH-binding protein
    • Binding stimulates production of IGF-1 and IGFBP-3
  • GH is secreted in pulsatile fashion – natural impetus for secretion is sleep
    • GH rises at night and sporadically during the day, possibly in relation to meals
    • GH increases in response to hypoglycemia

Clinical Presentation

Pediatrics

Epidemiology

  • Prevalence – 1:4,000 to 1:10,000
  • Age – often recognized in first 1-2 years
  • Sex – M>F

Clinical Presentation

  • Short stature (≥2 standard deviations below the mean for individuals of the same sex and chronological age)
  • Severe growth failure
  • Delayed bone age

Pathophysiology

  • May be due to deficiencies in the GH/IGF axis, but multiple other mechanisms can contribute to short stature (refer to Differential Diagnosis)
  • Main effect of GH is to promote growth of body tissues
    • Rate of growth in a child with deficiency is slow; however, growth is proportional
    • Intelligence appears unaffected

Monitoring

  • Linear height velocity usually accelerates with GH replacement – may not occur in ISS
  • Repeat GH testing
    • Only necessary after puberty to assess need for lifelong GH supplementation
  • IGF-1 or IGFBP-3 – refer to Monitoring

Indications for Testing

  • Short stature (≥2 standard deviations below mean, or third percentile)
  • Severe growth deceleration
  • History of surgery or irradiation to hypothalamus or pituitary gland
  • Radiologic evidence of structural hypothalamic-pituitary disease
  • History of traumatic brain injury or subarachnoid hemorrhage
  • Neonatal signs of GHD – hypoglycemia, jaundice, microphallus, or craniofacial midline abnormalities

Laboratory Testing

  • Caution is recommended in evaluation of GHD in children with short stature – most common cause is idiopathic short stature (ISS)
  • Chromosome analysis (karyotype), chromosomal microarray, or molecular DNA testing
    • Can assist with diagnosis in some cases (Seaver, 2009)
    • Test selection depends on specific clinical findings/features
  • Refer to Laboratory Testing in Diagnosis for testing recommendations

Differential Diagnosis

  • Select genetic disorders – relatively common causes of short stature beyond first 1-2 years
  • Endocrine disorders – much less common causes of short stature
    • Cushing syndrome
    • Hypogonadism
    • Hypothyroidism
    • GH insensitivity
  • Chronic systemic disorders
  • Etiologies of short stature
    • Normal variants of growth (eg, familial short stature)
    • Systemic disorders with secondary effects on growth (eg, cancer, cardiac disease)
    • Endocrine causes of growth failure (eg, Cushing syndrome, hypothyroidism)
    • Genetic diseases with primary effects on growth (eg, Turner syndrome [females], SHOX-related disorders, Noonan syndrome)
    • Skeletal dysplasias (eg, achondroplasia, osteogenesis imperfecta)

ARUP Lab Tests

Aid in diagnosis of GH excess or deficiency disorders

Aid in diagnosis of GH excess or deficiency disorders

Not a first-line test in the evaluation of growth disorders

Aid in workup of suspected anterior hypopituitarism

Related Tests

May be used as an adjunct to IGF-1 in diagnosis of growth disorders

Use for research interest only

For suspected GH disorders, IGF-1 and GH tests are recommended

Assess thyroid function

Identify risk in patients with palpable thyroid nodules

Preferred test for screening and monitoring of thyroid function

Aid in the diagnosis of adrenal insufficiency and determining the presence of anterior pituitary tumors

Confirm diagnosis of a known aneuploid syndrome or detect a chromosome translocation

This test is intended for constitutional studies

Useful for diagnosis of short stature in females with suspected Turner syndrome

Does not detect small rearrangements, submicroscopic deletions/duplications, or low-level mosaicism

Preferred first-tier test for developmental delay, multiple anomalies, and autism spectrum disorders

Testing is performed on peripheral blood

For diagnosis of individuals, both males and females, with short stature and other clinical features (eg, dysmorphic features, autism spectrum disorders, congenital malformations)

Areas of homozygosity may be suggestive of uniparental disomy or consanguinity

Does not detect all forms of polyploidy, balanced rearrangements (eg, inversions and balanced chromosomal translocations), small deletions, point mutations, and some mosaic conditions

Most comprehensive molecular genetic test to confirm clinical suspicion of a SHOX-related disorder

Medical Experts

Contributor
Contributor
Contributor

Young

Brittany A. Young, MD, PhD
Assistant Professor of Clinical Pathology at University of Utah
Co-Director of Clinical Laboratories at University Hospital, ARUP Laboratories

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®