Growth Hormone Deficiency

  • Diagnosis
  • Monitoring
  • Background
  • Pediatrics
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Evidence of structural hypothalamic-pituitary disease
  • Signs and symptoms of pituitary dysfunction in adulthood
  • Symptoms suggestive of growth hormone deficiency (GHD) – loss of muscle mass, central adiposity, low bone density, fatigue, and insomnia
  • History of surgery or irradiation to hypothalamus or pituitary gland

Laboratory Testing

Static Growth Hormone Testing

Test

Uses

Limitations

Growth hormone (GH)

Aid in diagnosis of GH excess or deficiency disorders

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

Insulin-like growth factor 1 (IGF-1)

Mediates growth-promoting effects of GH

Concentrations are less variable than GH concentrations

Low concentrations

  • Low IGF-1 and GH stimulation response – diagnostic of GHD
  • Severely low IGF-1 – diagnostic of GHD

Low concentration

  • Suggestive of GHD, but insufficient to diagnose GHD
  • May be secondary to uncontrolled diabetes, liver disease, or oral estrogen therapy

Normal concentration

  • Does not rule out GHD

Insulin-like growth factor binding protein 3 (IGFBP-3)

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

  • Concentrations reflect IGF-1 concentrations

Binds with IGF-1 in plasma

Low concentration

  • Suggestive of GHD, but insufficient to diagnose GHD

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

 

Stimulation Testing

One positive 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

Test

Uses

Protocol

Limitations

Insulin tolerance test (ITT)

Recommended test; has sufficient sensitivity and specificity (Endocrine Society, 2011; The Growth Hormone Research Society, 2007)

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

Diagnostic – GH <4 ng/mL

Requires constant monitoring

Not indicated

  • Elderly (>60 years)
  • Patients with diabetes, severe seizure disorders, or ischemic heart disease

Several studies question reproducibility and specificity

Glucagon

Recommended when growth hormone releasing-hormone (GHRH) not available and ITT contraindicated or not practical (Endocrine Society 2011)

Suitable alternative when GHRH or growth hormone releasing hexapeptide (GHRP) not available and ITT contraindicated (The Growth Hormone Research Society 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, may also measure at 220 and 240 minutes

Less diagnostic value than ITT

 

Not indicated in patients with malnutrition, pheochromocytoma, or insulinoma

Performance in diabetic patients is unknown

GHRH

Recommended test; has sufficient sensitivity and specificity (Endocrine Society, 2011; The Growth Hormone Research Society, 2007)

 

Currently unavailable in the U.S.

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

Imaging Studies

  • If no obvious etiology of GHD
    • Magnetic resonance imaging (MRI) of head without contrast
    • CT of head
      • Acceptable if MRI is contraindicated or not available
  • Insulin-like growth factor 1 (IGF-1) or insulin-like factor binding protein (IGFBP-3)
    • Use for dose titration
    • Monitor patient every 1-2 months until an appropriate concentration is reached, then at 6-month intervals

Growth hormone deficiency (GHD) in adults is most commonly due to pituitary damage by trauma, compression, or radiation therapy. It is the most common hormone deficiency associated with pituitary dysfunction, occurring in 61–100% of individuals with pituitary hormone deficiency. 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.

Epidemiology

Prevalence – rare in adults

Pathophysiology

  • GH is secreted by somatotropic cells of the anterior pituitary gland
    • Secretion is stimulated by GH-releasing hormone released by hypothalamus
    • GH binds to transmembrane receptors on target cells with GH-binding protein
    • Binding stimulates production of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3)
  • GH is secreted 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

Clinical Background

Epidemiology

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

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

  • May be due to deficiencies in the growth hormone (GH)/IGF axis, but multiple other mechanisms can contribute to short stature (refer to Differential Diagnosis section)
  • 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

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
  • History of traumatic brain injury or subarachnoid hemorrhage
  • Neonatal signs of growth hormone deficiency (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
  • Refer to Laboratory Testing discussion in Diagnosis section for testing recommendations

Differential Diagnosis

  • Most common causes of short stature beyond the first 1-2 years are
    • Familial short stature (genetic) – Turner syndrome most common (refer to “Genetic diseases with primary effects on growth” table below)
    • Constitutional
  • Endocrine causes (including GHD) – much less common causes of short stature
  • Endocrine disorders
  • Chromosomal disorders – often bone developmental delay
  • Chronic systemic disorders
  • Skeletal disorders
    • Achondroplasia
  • Etiologies of short stature

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
  • Insulin-like growth factor 1 (IGF-1) or insulin-like factor binding protein (IGFBP) – refer to Monitoring section
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.

Growth Hormone 0070080
Method: Quantitative Chemiluminescent Immunoassay

Limitations 

Low or normal value does not rule out growth hormone deficiency (GHD)

IGF-1 (Insulin-Like Growth Factor 1) (Inactive as of 11/13/17: Refer to 2007698 in the November Hotline) 0070125
Method: Quantitative Chemiluminescent Immunoassay

Limitations 

Normal concentration does not rule out GHD deficiency

Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3) 0070060
Method: Quantitative Chemiluminescent Immunoassay

Limitations 

Normal value does not rule out GHD

Guidelines

Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, Chernausek SD, Savage MO, Wit JM, 2007 ISS Consensus Workshop participants. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab. 2008; 93(11): 4210-7. PubMed

Federico G, Street ME, Maghnie M, Caruso-Nicoletti M, Loche S, Bertelloni S, Cianfarani S, Study Group on Physiopathology of growth processes, Council of ISPED. Assessment of serum IGF-I concentrations in the diagnosis of isolated childhood-onset GH deficiency: a proposal of the Italian Society for Pediatric Endocrinology and Diabetes (SIEDP/ISPED). J Endocrinol Invest. 2006; 29(8): 732-7. PubMed

Giustina A, Barkan A, Chanson P, Grossman A, Hoffman A, Ghigo E, Casanueva F, Colao A, Lamberts S, Sheppard M, Melmed S, Pituitary Society, European Neuroendocrine Association. Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults. J Endocrinol Invest. 2008; 31(9): 820-38. PubMed

K Y Ho K, 2007 GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, J Eur J Endocrinol. 2007; 157(6): 695-700. PubMed

Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML, Endocrine Society. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96(6): 1587-609. PubMed

General References

Audí L, Fernández-Cancio M, Camats N, Carrascosa A. Growth hormone deficiency: an update. Minerva Endocrinol. 2013; 38(1): 1-16. PubMed

Bidlingmaier M, Freda PU. Measurement of human growth hormone by immunoassays: current status, unsolved problems and clinical consequences. Growth Horm IGF Res. 2010; 20(1): 19-25. PubMed

Casanueva FF, Castro AI, Micic D, Kelestimur F, Dieguez C. New guidelines for the diagnosis of growth hormone deficiency in adults. Horm Res. 2009; 71 Suppl 1: 112-5. PubMed

Gasco V, Corneli G, Rovere S, Croce C, Beccuti G, Mainolfi A, Grottoli S, Aimaretti G, Ghigo E. Diagnosis of adult GH deficiency. Pituitary. 2008; 11(2): 121-8. PubMed

Hazem A, Elamin MB, Malaga G, Bancos I, Prevost Y, Zeballos-Palacios C, Velasquez ER, Erwin PJ, Natt N, Montori VM, Murad MH. The accuracy of diagnostic tests for GH deficiency in adults: a systematic review and meta-analysis. Eur J Endocrinol. 2011; 165(6): 841-9. PubMed

Kargi AY, Merriam GR. Testing for growth hormone deficiency in adults: doing without growth hormone-releasing hormone. Curr Opin Endocrinol Diabetes Obes. 2012; 19(4): 300-5. PubMed

Stanley T. Diagnosis of growth hormone deficiency in childhood. Curr Opin Endocrinol Diabetes Obes. 2012; 19(1): 47-52. PubMed

Şiklar Z, Berberoğlu M. Syndromic disorders with short stature. J Clin Res Pediatr Endocrinol. 2014; 6(1): 1-8. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Grönbladh A, Johansson J, Kushnir MM, Bergquist J, Hallberg M. The impact of nandrolone decanoate and growth hormone on biosynthesis of steroids in rats. Steroids. 2013; 78(12-13): 1192-9. PubMed

Owen WE, Roberts WL. Performance characteristics of the IMMULITE 2000 insulin-like growth factor binding protein-3 assay. Clin Chim Acta. 2005; 353(1-2): 141-5. PubMed

Medical Reviewers

Content Reviewed: 
June 2017

Last Update: September 2017