Growth Hormone Deficiency

Primary Author: Meikle, A. Wayne, MD.

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

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

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
  • 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

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

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) – Turner syndrome is most common (see Genetic diseases with primary effects on growth table below)
    • Constitutional
  • Endocrine causes, including GHD, are much less common causes of short stature

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

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 GHD deficiency

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

Limitations

Normal value does not rule out GHD deficiency

Follow Up

May be used in conjunction with IGFBP-3

IGF Binding Protein-3 0070060
Method: Quantitative Chemiluminescent Immunoassay

Limitations

Normal value does not rule out GHD deficiency

Follow Up

May be used in conjunction with IGF-1

Related Tests

Guidelines

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

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 MLee, 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

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 MHassan. 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

Last Update: February 2016