- The strongest recommendations, reflecting high quality of supporting evidence, were:
- Growth hormone deficiency (GHD)
- Growth hormone (GH) should be used to normalize adult height and avoid extreme shortness in children and adolescents with GHD
- GH provocative test results should not be relied on as the sole diagnostic criterion of GHD
- GH assays should be harmonized
- GH recipients should be monitored regularly for potential development of intracranial hypertension, slipped capital femoral epiphysis (SCFE), and scoliosis progression
- Primary IGF-I deficiency (PIGFD)
- Insulin-like growth factor (IGF-I) therapy should be used to increase height in patients with severe PIGFD.
- Safety monitoring during treatment with IGF-I should include the risk for hypoglycemia.
- All other recommendations, including those for treating idiopathic short stature, received weaker recommendations due to uncertainty about the supporting evidence.
- Important evidence gaps persist related to diagnostic limitations, appropriate outcome measures, and long-term post-treatment safety of GH treatment.
Also discussed in the guideline:
- The balance of benefit, risk, and cost of GH treatment
- The expansion of use of growth-promoting treatment
- Conclusions and future directions
Evidence Quality and Recommendation Grades
Quality of Evidence
Strength of Recommendation
“The PES recommends”
“The PES suggests”
Ungraded good practice statement
Consideration And Diagnosis of Growth Hormone Deficiency (GHD)
Conditions Where GH Provocative Testing is Not Required to
Of note, for patients who do not meet the following criteria yet present a high index of suspicion, GHD can be diagnosed by the conventional approach.
- The Pediatric Endocrine Society (PES) suggests establishing a diagnosis of GHD without GH provocative testing in patients possessing all of the following three conditions: auxological criteria, hypothalamic-pituitary defect (such as major congenital malformation [ectopic posterior pituitary and pituitary hypoplasia with abnormal stalk], tumor or irradiation), and deficiency of at least one additional pituitary hormone. (C, ●●○○)
- The PES suggests that GHD due to congenital hypopituitarism be diagnosed without formal GH provocative testing in a newborn with hypoglycemia who does not attain a serum GH concentration above 5 μg/L and has deficiency of at least one additional pituitary hormone and/or the classical imaging triad (ectopic posterior pituitary and pituitary hypoplasia with abnormal stalk). (C, ●●○○)
Technical remark: A low GH concentration at the time of spontaneous hypoglycemia is alone insufficient to diagnose GHD.
GH Provocative Testing
- The PES recommends against reliance on GH provocative test results as the sole diagnostic criterion of GHD. (S, ●●●●)
- Very low peak GH levels on provocative testing are consistent with severe GHD, and patients with such results are expected to benefit greatly from GH treatment. However, the threshold test result that distinguishes normal from partial GHD that responds to treatment has not been well established.
- Given the substantial number of healthy, normally growing children who test below accepted limits, inadequate response to two different provocative tests is required for diagnosis of GHD. While it is possible that combining tests might yield different results from tests performed on separate days, there is no evidence against performing both tests sequentially on the same day.
- GH responses to provocative testing are blunted in obese or overweight individuals, and the peak values decrease with increasing body mass index (BMI). Unlike adults, obesity-dependent modifications to diagnostic criteria in children are undetermined.
- Given the large discrepancies between GH assays, the PES recommends that institutions require laboratories to provide harmonized GH assays using the somatropin standard, IRP IS 98/574, 22k rhGH isoform, as recommended by the 2006 and 2011 consensus statements, and the commutability standards recently outlined by Ross, et al. (Clin Chim Acta 2014;432:72-76). (S, ●●●●)
- The PES suggests sex steroid priming prior to provocative GH testing in pre-pubertal boys age >11 and in pre-pubertal girls age >10 years with adult height prognosis within -2 SD of the reference population mean in order to prevent unnecessary GH treatment of children with constitutional delay of growth and puberty. (C, ●●○○)
- Best available evidence exists for boys; evidence is extrapolated to girls.
- A reasonable approach in both boys and girls would be 2 mg (1 mg for body weight
<20 kg) of β-estradiol (not ethinyl estradiol) orally on each of the two evenings preceding the test. Alternatively, boys can be primed with intramuscular testosterone (50–100 mg of a depot formulation administered 1 week before the test).
- This recommendation applies to GH-naïve patients; it does not retroactively apply to patients already on GH treatment.
Measurement of Spontaneous GH Secretion
- The PES recommends against the use of spontaneous GH secretion in the diagnosis of GHD in a clinical setting. (S, ●●○○)