Growth Hormone Deficiency

Vijayakumar Madhava
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Diagnostic Evaluation
Careful history and auxological measurements help to differentiate pathological short stature from genetic & constitutional delay in growth and puberty. Wasting will be more pronounced in undernutrition. Carefully rule out any systemic organic diseases or chronic infections before doing investigations for growth hormone deficiency. Hypothyroidism is a more common endocrine cause in our country where new born screening program is not practiced. (Table 4) Bone age is characteristically delayed in congenital GH deficiency. Typically radiology of hand bones are used for calculating bone age

Table 4 : Investigations to rule out systemic diseases
Investigation Disease screened
Hemoglobin, peripheral smear Chronic anemias (iron deficiency anemia, hemolytic anemia, chronic infections)
ESR Chronic infection, inflammation
Blood urea, serum creatinine Chronic kidney disease
Calcium, phosphorous, alkaline phosphatase Rickets , pseudo hypoparathyroidism
SGPT, serum proteins Chronic liver diseases
ABG, Venous PCO2, bicarbonates Renal tubular acidosis
Blood glucose Diabetes Mellitus
Thyroid function tests Hypothyroidism
Tissue transglutaminase Celiac disease
Urine microscopy RTA, Chronic glomerulonephritis, chronic pyelonephritis
Stool –cysts Giardiasis
X-ray Hand – rickets, skull- supracellar calcifications, craniopharyngioma


Assessment of Pituitary Growth hormone production
Accurate assessment of growth hormone production is not easy owing to the pulsatile nature of growth hormone secretion. Between normal pulses of secretion, serum levels of growth hormone are very low. Hence measurement of random GH estimation is useless. Measurement of growth hormone reserve is done by using physiological and pharmacological stimuli. These tests called as “provocative tests” or “stimulation tests” are the basic tests for diagnosing GH deficiency. Stimulation tests include using physiologic stimuli like fasting, sleep and exercise or pharmacologic stimuli like levodopa, clonidine, glucagon, propranolol, arginine and insulin. For a child to be diagnosed as having growth hormone deficiency if he/she fails stimulation tests with at least 2 separate stimuli. (Table 5)

Table 5: Growth hormone stimulation tests (Modified from Pediatric Endocrinology : Mark A Sperling: 4th edition)
Stimulus Dosage Samples ( minutes) Comments
Levodopa (PO) < 15 kg – 125 mg
15- 30 kg – 250 mg
>30 kg - 500 mg
0,60,90 Nausea, vomiting, headache
Clonidine (PO) 0.15 mg/m2 0,30,60,90 Tiredness, postural hypotension
Arginine HCL (IV) 0.5 g/kg ( max 30 g) 10% arginine HCL in 0.9% saline over 30 minutes 0,15,30,45,60 Late hypoglycemia
Insulin (IV) 0.05-0.1 IU/kg 0,15,30,45,60,75,90,120 Hypoglycemia
Glucagon ( IM) 0.03 mg/kg (max 1 mg) 0,30,60,90,120,150,180 Nausea
Procedure
• Euthyroid state is essential before testing
• Test should be done after an overnight fast
• Peripubertal children (bone age > 10 years) should be primed with sex steroids. Premarin 5 mg PO, the night before and the morning of the test in girls and depot testosterone 100 mg 3 days before testing in boys
• Close monitoring with BP, heart rate and IV saline administration in case of hypotension if clonidine is used. Monitoring blood sugars and administering 10% dextrose and glucagon in case of hypoglycemia if insulin is used
• 2 standard stimulation tests are usually recommended


Disadvantages of provocative tests
None of the provocative tests mimics the normal secretary pattern of growth hormone. They have poor reproducibility.

Interpretation of results

In general the results are interpreted as follows
• Severe deficiency : GH stimulated levels < 5 ng/ml
• Mild to moderate deficiency : GH levels 5-10 ng/ml
• Severe deficiency : GH levels > 10 ng/ml

Measurement of IGF1 and IGFBP3 can reflect the growth hormone status of the patient. Their serum levels remain constant throughout the day hence a single reading suffices. But these measurements have some limitations. IGF-1 concentrations are age dependent. (Table 6) They are lowest in young children. Their serum concentration will be affected by various conditions. Malnutrition, mal absorption (e.g.; Celiac disease), type 1 diabetes etc will cause a reduction in serum IGF-1 levels. Age dependent variations in the levels of IGFBP3 are less marked; hence it is a more dependable marker of GH deficiency in young age including infants. (Table 7) More over its levels are not much affected by nutritional status, unlike the levels of IGF-1. IGFBP3 levels are clearly growth hormone dependent.

Table 6: Serum levels of IGF-1 in different age groups (adapted from Harriet Lane 19th Ed: 2012:267-268)
Age Boys (male) ng/ml Girls ( females) ng/ml
2 mo – 6 yr 17-248 17-248
6 - 9yr 88- 474 88- 474
9 - 12 yr 110 – 565 117 - 771
12 – 16 y 202- 957g 261 - 1096
16- 26 yr 182 – 780 182- 780


Table 7: Serum levels of IGF-BP3 in different age groups (adapted from Harriet Lane 19th ed :2012 :267-268)
Age Boys (male) ng/ml Girls ( females) ng/ml
0-2 0.94 – 1.76 0.66 – 2.51
2-4 1.12 – 2.33 0.84 – 3.77
4- 6 1.16 – 3.13 1.32 – 3.60
6- 8 1.32 – 3.38 1.21 – 4.66
8- 10 1.35 – 3.94 1.58 – 3.99
10-12 1.53 -5.02 1.93 – 6.46
12 -14 1.73 -5.11 1.78 – 6.08
14 -16 1.90 -6.40 2.02- 5.44
16 -18 1.70 – 6.04 1.88 – 5.29



Role of imaging
An MRI of brain with particular emphasis on hypothalamus and pituitary gland should be done in all children diagnosed as having growth hormone deficiency. In children < 10 year a normal pituitary gland has a length of 5-6 mm in the vertical axis. In hypopituitarism in addition to a small pituitary gland absence of pituitary stalk and ectopic position of posterior pituitary bright spot may be seen. An imaging also helps to find out intra cranial tumors or congenital anomalies like septo-optic dysplasia

Assessment of other pituitary hormonal status
Low T4 or free T4 and low /low normal TSH level are suggestive of central hypothyroidism. Prolonged response to TRH is seen in this situation. Low basal cortisol and poor cortisol response to ACTH is suggestive of defect in cortisol production. Unless cortisol is supplemented, it results in adrenal crisis. LH, FSH, testosterone/estradiol estimation is done if they present with pubertal delay. Low ADH levels denoted by high sodium levels, high plasma and low urine osmolality warrants further investigations for posterior pituitary function. Low prolactin levels are seen in some forms of Growth hormone deficiency disorders (PIT-1 gene defect). Its levels are high in intracranial tumors.

Testing a neonate
Presence of micropenis, midline defects or a resistant hypoglycemia warrants evaluation for growth hormone axis. GH stimulation testing can’t be done in a neonate. In the presence of hypoglycemia, measurement of GH from a critical sample almost mimics a GH stimulation test. A Growth hormone level less than 20 ng/ml is suggestive of Growth hormone deficiency in a neonate.

Growth hormone insensitivity
A combination of normal growth hormone levels in stimulation tests combined with low serum IGF-1 and IGF BP3 levels in a short child (in whom nutritional and systemic disorders are ruled out) is suggestive of growth hormone insensitivity. The levels of IGF-1 will remain low even after growth hormone supplementation for one week (IGF-1 generation test). Treatment option for GH insensitivity is IGF1.

Evaluation for genetic disorders
Recently detection of correct genetic cause for short stature is possible in research laboratories. Pointers to a possible genetic etiology are:
• Early onset of growth failure
• Positive family history
• Consanguinity
• Associated congenital anomalies ( septo -optic dysplasia, midline defects, single central incisor)
• Severe short stature ( height > 3SD below mean)
• Very low GH response to provocation, very low IGF-1 and IGF-BP3 levels


References
Growth Hormone Deficiency Growth Hormone Deficiency 4/4/2016
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