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 in adults

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

• Constitutional – fatigue, low self-esteem
• Increased body fat, reduced lean mass
• Reduced exercise capacity
• Dyslipidemia
• Complications – coronary artery disease, hypertension, insulin resistance, osteopenia

Treatment

• GH replacement

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  
  • Indications other than GH deficiency include the following
    • 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 include the following
        • 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

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
  • Hypothyroidism
  • Chromosomal disorders
    • Prader-Willi syndrome
      • Genetic disorder involving deletion of long arm of chromosome 15
      • Incidence – 1/15,000
      • Age-specific symptoms
        • Infants – hypotonic with poor feeding
        • Two years – hyperphagic, short stature
        • Complications as adults – prone to diabetes mellitus type 2, morbid obesity, hypogonadism
    • Turner syndrome
      • Chromosomal abnormality
      • Incidence – 1/2,000 live births
      • Short stature and infertility
    • Chronic systemic disease
      • Renal failure is most common
      • Malabsorption (celiac disease)
  • Skeletal disorders
  • ISS

Laboratory Testing

• Initial serum GH concentrations cannot be used alone to diagnose deficiency due to pulsatile nature of GH release; also 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
• GHRH plus arginine – method of choice
  • Other agents include L-dopa, arginine, clonidine and glucagon
  • Normal stimulation result in children is GH >7 ng/mL
    • Some experts consider values of 5-7 ng/mL equivocal and only peak values >7 ng/mL as truly normal
• Results suggestive of GH deficiency following stimulation tests
  • IGF-1 or IGFBP-3 measurement – low

Indications for Testing

• Evidence of hypothalamic-pituitary disease (GH deficiency in childhood, signs and symptoms of pituitary dysfunction in adulthood)

Laboratory Testing

• Diagnosis may require 2 positive stimulation tests (1 positive stimulation test is sufficient according to 2007 Growth Hormone Research Society Workshop Statement)
  • GH stimulation – insulin-induced hypoglycemia (ITT) or GHRH plus arginine stimulation recommended tests for adults
  • ITT is test of choice – GH <4 ng/mL is diagnostic
    • GHRH plus arginine (GH <3 ng/mL is diagnostic)
    • Arginine or glucagon stimulation alone might be alternatives
  • Results of all tests affected by obesity
• Arginine stimulation test with GHRH
  • 0.5 g/kg body weight IV arginine plus GHRH given over 30 minutes with serum GH at 0, 30, 60, 90 minutes; positive test is GH <3 ng/mL
    • Normal – >5 ng/mL in adults
  • Not as accurate as ITT in adults  – different cutoff values depending on BMI
  • May be performed with GHRH
  • Not affected by age
• Results suggestive of GH deficiency following stimulation tests – IGF-1 (low), IGFBP-3 (low)
  • Severely low concentrations of IGF-1 can be used as evidence for GH deficiency
• Deficiencies in other anterior pituitary hormones can occur with low IGF-1
  • Consider testing for LH/FSH, TSH, ACTH

Imaging Studies

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

• 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   

Tests generally appear in the order most useful for common clinical situations

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 :112-115.PubMed
• Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, Chernausek SD, Savage MO, Wit JM. 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) :4210-4217.PubMed
• Federico G, Street ME, Maghnie M, Caruso-Nicoletti M, Loche S, Bertelloni S, Cianfarani S. 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) :732-737.PubMed
• Giustina A, Barkan A, Chanson P, Grossman A, Hoffman A, Ghigo E, Casanueva F, Colao A, Lamberts S, Sheppard M, Melmed S. Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults. J Endocrinol Invest. 2008; 31 (9) :820-838.PubMed
• Ho KK. 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, Japan Endocrine Society, and Endocrine Society of Australia. Eur J Endocrinol. 2007; 157 (6) :695-700.PubMed
• Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Shalet SM, Vance ML, Stephens PA. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2006; 91 (5) :1621-1634.PubMed
• Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96 (6) :1587-1609.PubMed

General

• 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
• Biller BM. Concepts in the diagnosis of adult growth hormone deficiency. Horm Res. 2007; 68 Suppl 5 :59-65.PubMed
• Clemmons DR. Clinical utility of measurements of insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab. 2006; 2 (8) :436-446.PubMed
• Gabellieri E, Chiovato L, Lage M, Castro AI, Casanueva FF. Testing growth hormone deficiency in adults. Front Horm Res. 2010; 38 :139-144.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) :121-128.PubMed
• Ghigo E, Aimaretti G, Corneli G. Diagnosis of adult GH deficiency. Growth Horm IGF Res. 2008; 18 (1) :1-16.PubMed
• Kaushal K, Shalet SM. Defining growth hormone status in adults with hypopituitarism. Horm Res. 2007; 68 (4) :185-194.PubMed
• Laursen T, Jorgensen JO, Christiansen JS. The management of adult growth hormone deficiency syndrome. Expert Opin Pharmacother. 2008; 9 (14) :2435-2450.PubMed
• Richmond EJ, Rogol AD. Growth hormone deficiency in children. Pituitary. 2008; 11 (2) :115-120.PubMed
• Rosenfeld R, Allen DB, MacGillivray MH, Alter C, Saenger P, Anhalt H, Hintz R, Katz HP. Growth hormone use in pediatric growth hormone deficiency and other pediatric growth disorders. Am J Manag Care. 2000; 6 (15 Suppl) :S805-S816.PubMed

ARUP Institute for Clinical and Experimental Pathology®

• 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) :141-145.PubMed

Amenorrhea
Hypogonadism, Male
Hypopituitarism
Prader-Willi Syndrome
Thyroid Disease