growth%20hormone%20deficiency
GROWTH HORMONE DEFICIENCY
Growth hormone deficiency in adults reflects an absence of two hormones, growth hormone and insulin-like growth factor-1 (IGF-1), affecting the process of glucose-insulin metabolism, lipolysis and bone remodelling.
History may show pituitary adenoma, surgery &/or radiation treatment of pituitary adenomas or cranial radiation for other disorders, deficiency of other pituitary hormones that may occur concurrently with growth hormone deficiency, and previous childhood growth hormone deficiency.
Physical exam reveals reduced lean body mass with increased weight, body fat predominantly in the abdominal region, thin & dry skin, cool peripheries, poor venous access and blunt affect.

Growth%20hormone%20deficiency Diagnosis

History

Adults

  • Pituitary adenoma
  • Surgery and/or radiation treatment of pituitary adenomas or cranial radiation for other disorders
  • Deficiency of other pituitary hormones may occur concurrently with growth hormone deficiency (GHD)
  • Previous childhood GHD

Children

  • Any of the following may indicate GHD:
    • In the neonate: Hypoglycemia, prolonged jaundice
    • History of microphallus or traumatic delivery
    • Head trauma, central nervous system (CNS) infection or cranial radiation
    • Consanguinity and/or affected family member
    • Craniofacial midline abnormalities

Physical Examination

Adults

  • Reduced lean body mass with increased weight, body fat predominantly in the abdominal region
  • Thin and dry skin
  • Cool peripheries
  • Poor venous access
  • Blunt affect

Children

  • Height and weight evaluation
    • Plot weight and height measurements on growth charts which will graphically depict changes in growth and growth velocity
  • Short stature may suggest growth hormone deficiency (GHD) and immediate investigation should be conducted if any of the following criteria are present:
    • Severe short stature [defined as height >3 standard deviation (SD) below population mean]
    • Height >2 SD below population mean with 1-year height velocity >1 SD below mean for chronological age or (in child age >2 year), a 1-year decrease of >0.5 SD in height
    • In the absence of short stature, a 1-year height velocity >2 SD below the mean or a 2-year height velocity >1.5 SD below the mean (especially GH manifesting during infancy or in organic acquired GHD)
    • Height >1.5 SD below midparental height: Male [(paternal height in cm) +(maternal height in cm + 13)] divided by 2; female [(paternal height in cm - 13) + (maternal height in cm)] divided by 2
    • Signs indicative of an intracranial lesion
    • Signs of multiple pituitary hormone deficiencies (MPHD)
    • Neonatal signs and symptoms of GHD
  • Other clinical features/findings of growth hormone deficiency (GHD) in children
    • Increased subcutaneous fat, especially around the trunk
    • Lower body mass index (BMI) and waist-to-hip ratio compared with adult onset growth hormone deficiency (AOGHD)
    • Immature facies, with a prominent forehead and depressed midfacial development
    • Delayed dentition
    • Delayed average age of pubertal onset
    • In males, the phallus may be small
    • Lower serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels compared with AOGHD
    • More reduced muscle and bone mass, and reduced cardiac function as compared with AOGHD

Laboratory Tests

Adults

  • Diagnosis of growth hormone deficiency (GHD) is based on subnormal growth hormone (GH) secretion in response to a stimuli
    • There are various stimulation tests available for the diagnosis of GHD
  • Insulin tolerance test (ITT)
    • Gold standard test for diagnosing adult GHD
    • Insulin-induced hypoglycemia provides strong stimulus for GH secretion
    • Contraindicated in seizures, cardio/cerebrovascular disease, elderly >60 years
    • Should only be performed in specialized endocrine units
  • Serum IGF-1 concentration is also used to confirm GHD: Decreased levels than the gender- and age-specific lower limit of normal is confirmatory of GDH
  • Acceptable alternative stimulation tests include:
    • Growth hormone–releasing hormone (GHRH) + Arginine (ARG) test
      • Traditionally, the alternative test of choice
      • In cases of hypothalamic GHD (where GHRH + ARG test may produce false-negative result), a normal test result warrants further testing (test of choice would be ITT, followed by glucagon or possibly, ARG alone)
    • ARG + Levodopa (L-dopa)
      • Alternative test used in the absence of GNRH
      • Highly sensitive (95%) but with low sensitivity (75%)
    • Glucagon test
      • Recommended alternative test when ITT is undesirable or when GHRH + ARG test is unavailable
      • In recent years, has been increasingly used in US and Europe as alternative test of choice due to unavailability of GHRH + Arg test in these regions
      • Other advantages include safety, reproducibility, lack of influence by gender and hypothalamic cause of GHD and relatively few contraindications
      • BMI-appropriate GH cut-off points are recommended to diagnose adult GHD
    • ARG test alone
      • Alternative when ITT and glucagon tests are unavailable
      • Use with caution since fewer data are available about its accuracy in GHD diagnosis
      • It should be limited to non-obese adolescents as it is very dependent on body mass index
    • Macimorelin test
      • Recommended alternative test when ITT is contraindicated or not possible
      • GH cut-off point: 2.8 mcg/L
      • Advantages include safety, high reproducibility, effectivity, excellent tolerability with minimal side effects, shorter duration of testing, no need for parenteral administration, and with sensitivity and specificity comparable to ITT
      • Further studies are needed to determine the safety profile and diagnostic value in children, adolescents, elderly, in patients with obesity, diabetes mellitus (DM), traumatic brain injury, subarachnoid hemorrhage, and renal or hepatic dysfunction
  • The following conditions are considered GH deficient and do not require further GH stimulation tests: Serum insulin-like growth factor (IGF-1) levels below the age- and sex-appropriate reference range when off GH therapy, irreversible hypothalamic-pituitary structural lesions and those with evidence of panhypopituitarism (at least 3 pituitary hormone deficiencies)
    • It is important to note that severe GHD may also be associated with normal serum IGF-1 levels (nearly always <50th percentile)
    • Clinicians should therefore consider GHD in a patient with an IGF-1 <50th percentile and perform further testing
  • Body mass index (BMI) should be used with GHRH + ARG test since BMI has a well-validated effect on GH responses to GHRH and ARG stimulation
  • Aneurysmal subarachnoid hemorrhage and traumatic brain injury may cause transient GHD; GH stimulation testing is therefore recommended to be done at least 12 months after the event

Children

  • Serum GH Level
    • In newborns, serum GH level <20 mcg/L is highly suggestive of GHD
      • GH level measured in neonates with hypoglycemia but no metabolic disorder
    • After the newborn period, random serum GH levels are not reliable indicators of GHD due to the pulsatile nature of GH secretion
  • GH Stimulation (Provocative) Tests
    • At least 2 provocative tests are ideal to ascertain the diagnosis due to high frequency of false-negative results
      • Minimum of 2 provocative tests with low peak levels of GH, poor linear growth, and delayed skeletal age is highly indicative of chronic GHD
      • Only 1 GH stimulation test is required in children with CNS pathology, cranial irradiation or genetic defects
    • Provocative tests in children with peak GH concentration <10 mcg/L supports GHD diagnosis:
      • Insulin tolerance test (ITT): GH level ≤5.0 mcg/L indicative of GHD; contraindicated in patients with cardiovascular disease, cerebrovascular disease and seizure disorders
      • GHRH with or without arginine: GH level <4.1 mcg/L indicates GHD in a GHRH-arginine test
      • Clonidine, Levodopa, Propranolol
      • Glucagon with or without beta-blockers: Peak GH of ≤3.0 mcg/L indicative of GHD and possible initiation of treatment
      • May consider sex steroid priming prior to conducting GH provocative test in prepubertal children (boys>11 years old and girls >10 years old) to improve diagnostic specificity
      • May choose not to proceed with this test if patients have other findings that clearly indicates GHD [pituitary abnormality, newborns with congenital pituitary abnormality, extreme short stature (height <-3 SD), significantly reduced IGF-1 and IGFBP-3 levels, and delayed bone age manifested by an infant or young child with no known nutritional deficiency]
  • Insulin-like Growth Factor-1 (IGF-1) or Somatomedin Test and Insulin-like Growth Factor Binding Protein-3(IGFBP-3) Test
    • Produced when the liver and other tissues are stimulated by GH
    • IGF-1 is a direct reflection of the concentrated level of functional GH secretion
      • More stable measurable concentrations compared to the pulsatile secretion of GH
    • IGFBP-3 is a major serum carrier protein for IGF-1 and is GH-dependent
      • Better differentiates low vs low-normal IGFBP-3 levels in young children compared to somatomedin test
    • Values ≥2 SD below the mean for IGF-1 or IGFBP-3 strongly suggest an abnormality in the GH axis, if other causes of low IGF have been excluded
    • However, normal values for IGF-1 and IGFBP-3 can be found in children with GHD
      • Low levels may be seen in patients with GH insensitivity, hypothyroidism, DM, renal failure, and malignancy
  • Other Tests
    • Acid-labile subunit test
      • Used to rule out postreceptor defects, specifically a dysfunction in the acid-labile subunit as a cause of IGF-1 deficiency
      • Postreceptor defects are more common in patients with GH resistance/insensitivity syndrome and not GHD
      • More studies are needed to establish the use of this test for IGF-1/IGFBP-3 level determination in GHD
    • Patients with GHD may have increased total cholesterol, low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B and triglyceride (TG) levels and decreased high-density lipoprotein-cholesterol (HDL-C)

Imaging

Children

  • Magnetic resonance imaging or computed tomography (MRI or CT) scans of the brain
    • Performed to define the anatomy of the hypothalamic-pituitary region and to identify intracranial tumors, optic nerve hypoplasia, septo-optic dysplasia or other structural or developmental anomalies
  • Radiograph studies to estimate bone age
    • Left wrist and hand for children 1 year of age or older
    • Knee and ankle for infants <1 year old
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