Growth Hormone Deficiency

Primary Author Meikle, A. Wayne, MD.

Key Points

Growth Hormone Deficiency Stimulation Testing

Growth hormone deficiency (GHD) leads to the development of significant comorbid diseases and reduced quality of life. The diagnosis of deficiency is difficult because GH is secreted in a pulsatile fashion; a single, random low GH test result 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.

Diagnosis of GHD 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 test (ITT) is recommended; when ITT is contraindicated, glucagon stimulation testing has adequate sensitivity and specificity for diagnosing GHD in adults. Caution is recommended in evaluation for GHD in children with short stature because the most common cause is idiopathic short stature (please refer to Pediatrics section). The test of choice in children is arginine stimulation.

Current Stimulation Testing Guidelines

Stimulation Test

Recommendations

Limitations

Insulin tolerance test (ITT) – evaluates the integrity of the hypothalamic-pituitary axis and simulates adrenocorticotrophin

  • Recommended test; has sufficient sensitivity and specificity (Endocrine Society 2011; The Growth Hormone Research Society 2007)
  • GH <4 ng/mL is diagnostic
  • Requires constant monitoring of patient
  • Not indicated in the elderly or in patients with  severe seizure disorders or ischemic heart disease
  • 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 (Endocrine Society 2011; The 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
  • Unaffected by age
  • Currently unavailable in the U.S.
  • Not useful if recent (<10 years) hypothalamic etiology (eg, irradiation) for GHD; results may be misleading (false-normal result)
  • GHD 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 (The Growth Hormone Research Society 2007; not addressed by Endocrine Society)
  • Currently unavailable in the U.S.
  • GHD 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 (Endocrine Society 2011)
  • Suitable alternative when GHRH or GHRP not available and ITT contraindicated (The Growth Hormone Research Society 2007)
  • Not indicated in patients with malnutrition, pheochromocytoma, or insulinoma
  • Performance in diabetic patients unknown

Additional Notes

  • Stimulation tests
    • One stimulation test is sufficient for diagnosing GHD in adults
    • Optional when patient has deficiencies in ≥3 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
  • Results that are diagnostic of GHD
    • Low IGF-1 and a low GH stimulation response
    • Severely low IGF-1
  • Results that are suggestive of GHD
    • Low IGF-1
    • Low insulin-like growth factor-binding protein 3 (IGFBP-3)
  • Results of all tests are affected by obesity
  • Deficiencies in other anterior pituitary hormones can occur with low IGF-1 –  consider testing for luteinizing hormone/follicle-stimulating hormone (LH/FSH), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH)

References:  Ho KK 2007; Kargi A 2012; Molitch ME et al 2011; Stanley T 2012

Diagnosis

Indications for Testing

Laboratory Testing

  • Refer to Key Points section for guideline recommendations regarding stimulation testing for growth hormone deficiency (GHD)

Imaging Studies

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

Monitoring

  • Linear height velocity usually accelerates with growth hormone (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 deficiency (GHD) is a condition usually acquired in adulthood.

Epidemiology

  • Prevalence – uncommon

Etiology (Acquired)

  • Acquired deficiency typically caused by damage to the pituitary gland; 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 of anterior pituitary function
        • Loss of GH, follicle-stimulating hormone (FSH), and luteinizing 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 is secreted by the anterior pituitary gland
    • 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

Pediatrics

Clinical Background

Epidemiology

  • Prevalence
    • Growth hormone deficiency (GHD) – rare
    • Idiopathic short stature – common
  • Age – often recognized in first 1-2 years
  • Sex – M>F

Etiologies of Short Stature

  • Two most common causes of short stature beyond the first 1-2 years
    • Familial short stature (genetic)
    • Constitutional
  • Endocrine causes, including GHD, are much less common causes of short stature
  • Normal variants of growth
    Normal Variants of Growth
    Growth PatternDistinguishing FeaturesBone AgeHeight Velocity
    Constitutional delay of growth and puberty

    Normal height for bone age but not for chronological age

    Often a family history of delayed growth and/or puberty

    Adult height usually normal

    Delayed

    Slow during first 3-5 years

    Pubertal growth spurt delayed but prolonged; often results in normal adult height

    Familial short stature

    Short parent(s), often <10th percentile

    Short adult height, but within range predicted by height of parent

    Normal

    Low to normal

    Girls – ~4-5 cm/year

    Boys – ~3.5-4.5 cm/year

    Infant is small for gestational age, with catch-up growthUsually catch up by 2 yearsNormalNormal
    Systemic disorders with secondary effects on growth

    Systemic Disorders with Secondary Effects on Growth

    Disease or Syndrome

    Distinguishing Features

    Bone Age

    Height Velocity

    Cancer (any type)Multiple mechanisms for failure to grow (eg, decreased intake of nutrients or increased energy needs)DelayedSlow
    Cardiac disease (any type, severe)

    Growth failure

    Anorexia; increased basal energy requirements

    Occasionally, growth delay is the presenting feature

    DelayedSlow
    Gastrointestinal (GI) disease (eg, Crohn or celiac disease)GI symptoms (abdominal pain, diarrhea)DelayedSlow
    Glucocorticoid therapyDose relatedDelayedSlow
    Immunologic diseaseRecurrent infectionsDelayedSlow

    Metabolic disease (inborn errors of metabolism)

    Multiple mechanisms for failure to grow (eg, decreased intake of nutrients or increased energy needs)DelayedSlow
    Pulmonary disease (eg, severe asthma, cystic fibrosis, immune deficiencies with recurrent pulmonary infections)Recurrent respiratory infections; other respiratory symptomsDelayedSlow
    Renal disease (eg, chronic kidney disease (CKD), renal tubular acidosis)Slow growth may precede diagnosis of CKDDelayedSlow
    Rheumatologic disease (eg, juvenile idiopathic arthritis)Arthralgias, rash, fever, lymphadenopathyDelayedSlow
    UndernutritionLow weight for heightDelayed or normalSlow
    Endocrine causes of growth failure

    Endocrine Causes of Growth Failure

    Syndrome

    Distinguishing Features

    Bone Age

    Height Velocity

    Prevalence

    Cushing syndromeObesity with fat distributed centrally; buffalo hump; purple striaeDelayedSlowRare
    Growth hormone deficiencyProgressive failure to grow; symptoms of other pituitary hormone deficienciesDelayedSlowUncommon
    HypothyroidismLethargy; sluggishness; cold intolerance; constipation; decreased reflexesDelayedSlowCommon
    Precocious pubertyEarly onset of secondary sexual developmentAdvancedInitially fast but stops early

    Common

    Predominance in females, particularly African American

    Genetic diseases with primary effects on growth

    Genetic Diseases with Primary Effects on Growth

    Syndrome

    Distinguishing Features

    Bone Age

    Height Velocity

    Incidence/Prevalence

    Bloom syndrome

    Short stature; sun-sensitive skin changes; increased risk of cancer

    Distinctive facial features

    Learning disabilities; increased risk of diabetes

    Recurrent respiratory infections during infancy

    Females – reduced fertility; males – infertile

    NormalLowRare outside of Ashkenazi Jews
    Noonan syndrome

    Short stature; heart disease; intellectual disability; webbed neck; minor facial dysmorphism

    Pectus excavatum or pectus carinatum; scoliosis; cryptorchidism

    NormalLow-normal or slow1/1,000-2,500
    Prader-Willi syndromeShort stature; developmental delay; hypogonadism; severe hyperphagia and obesityNormalSlow1/10,000-30,000
    Russell-Silver syndrome

    Slow growth before and after birth; failure to thrive; short stature; distinctive facial features (small, triangular face, narrow chin, small jaw)

    GI tract abnormalities; increased risk of delayed development and learning disabilities

    NormalSlow1/100,000
    SHOX-related haploinsufficiency

    Deletion of entire gene may cause idiopathic short stature with stocky appearance; possible subtle skeletal abnormalities

    Mutations may cause extreme shortening of long bones in arms and legs; Madelung deformity (abnormal wrist and forearm bones)

    NormalSlow1/4,000
    Turner syndrome (females)

    Short stature; loss of ovarian function; square chest; webbed neck; skeletal abnormalities; kidney and/or heart defect

    ≤50% of patients have only short stature and absent pubertal development

    NormalSlow1/2,500-3,000 live female births
    Skeletal dysplasias
    Skeletal Dysplasias
    ConditionDistinguishing FeaturesBone AgeHeight Velocity
    Achondroplasia

    Short-limbed dwarfism

    Inability of cartilage to form bone, especially in long bones of arms and legs; trident hands

    Mildly delayedSlow
    Hypochondroplasia

    Same features as achondroplasia, but generally much milder

    Macrocephaly; limitation in elbow extension

    NormalSlow
    Osteogenesis imperfecta

    Multiple bone fractures during childhood and adolescence or even prenatally

    Possible blue sclera; hearing loss; respiratory problems; short stature; scoliosis

    NormalLow-normal or slow
    Spondyloepiphysial dysplasia congenita

    Dwarfism; skeletal abnormalities; vision problems; hearing loss

    Average-sized hands and feet

    Kyphoscoliosis and lordosis can lead to breathing problems

    Broad, barrel-shaped chest; clubfoot deformity

    Possible spinal cord damage from instability of vertebrae in neck; arthritis;  decreased joint mobility

    NormalSlow

Clinical Presentation

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

Pathophysiology

  • Correlation between birth length and adult height is only .25
    • Not all genes that affect growth are expressed at birth
  • Three phases of growth
    • Infantile
      • Very rapid growth with gradual deceleration
    • Childhood
      • Relatively constant growth with slowing later until puberty
    • Pubertal
      • Growth spurt of 8-14 cm/yr
      • Growth due to synergist effects of gonadal steroids and GH
      • Girls – ~age 10
      • Boys – ~age 12

Diagnosis

Indications for Testing

  • Short stature (>2 standard deviations below mean, or <2.3 percentile)
  • Severe growth deceleration
  • History of brain tumor, irradiation
  • Radiologic evidence of pituitary abnormality

Laboratory Testing

  • Prior to GH testing – rule out all other causes of short stature
    • Endocrine disorders
    • Chromosomal disorders – often bone developmental delay
    • Chronic systemic disorders
    • Skeletal disorders
      • Achondroplasia
    • <1 percentile for height (defined as extreme short stature) – should be evaluated by specialist
    • If child appears to have idiopathic short stature (all other causes ruled out except GHD) and parental height suggests this
      • GH analysis may not provide information
      • Testing for GHD not recommended
  • GH 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
        • IGF-1 testing alone is insufficient to diagnose GHD
      • If GH concentrations remain low after stimulation, then GHD is confirmed
    • Growth hormone-releasing hormone (GHRH)  plus arginine – method of choice, but GHRH not available in U.S.
      • 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
    • Insulin tolerance test (ITT)  
      • Method – 0.1 unit of insulin/kg of body weight and measure GH at 0, 15, 30, 60, and 90 minutes

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 GHD deficiency

Low or normal value does not rule out GHD deficiency

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

Concurrent test for GHD deficiency

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

May be used to assess GHD deficiency

Normal value does not rule out GHD deficiency

May be used in conjunction with IGF-1
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Growth Hormone, 0 Minutes 0070081
Method: Quantitative Chemiluminescent Immunoassay

GH stimulation testing, specimen 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, specimen 2

Growth Hormone, 60 Minutes 0070083
Method: Quantitative Chemiluminescent Immunoassay

GH stimulation testing, specimen 3

Growth Hormone, 90 Minutes 0070084
Method: Quantitative Chemiluminescent Immunoassay

GH stimulation testing, specimen 4

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