Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-like Growth Factor-I Deficiency

Publication Date: January 1, 2017
Last Updated: December 16, 2022

Conditions Where GH Provocative Testing is Not Required to
Diagnose GHD

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 , ●●●● )

Technical remarks:

  • 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 , ●●○○ )

Technical remarks:

  • 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).
  • -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 , ●●○○ )


Efficacy of GH Treatment for GHD

The PES recommends the use of GH to normalize adult height and avoid extreme shortness in children and adolescents with GHD. ( S , ●●●● )

The PES suggests against routine cardiac testing, dual x-ray absorptiometry (DXA) scanning, and measurement of lipid profiles in children and adolescents treated with GH. ( S , ●●●● )

Dosing of GH Treatment for Patients With GHD

The PES recommends the use of weight-based or body surface area (BSA)-based GH dosing in children with GHD. ( S , ●●●○ )

Technical remark: The PES cannot make a recommendation regarding IGF-I-based dosing because there are no published adult height data using this method. The rationale is logical, but the target IGF-I level has not been established to optimize the balance between adult height gain, potential risks, and cost.


The PES recommends an initial GH dose of 0.16–0.24 mg/kg/week (22–35 μg/kg/day) with individualization of subsequent dosing. ( S , ●●○○ )
Technical remark: Some patients may require higher doses.

The PES suggests measurement of serum IGF-I levels as a tool to monitor adherence and IGF-I production in response to GH dose changes. The PES suggests that the GH dose be lowered if serum IGF-I levels rise above the laboratory-defined normal range for the age or pubertal stage of the patient. ( C , ●○○○ )

During puberty, the PES recommends against the routine increase in GH dose to 0.7 mg/kg/week in every child with GHD.

( S , ●●○○ )

The PES recommends that GH treatment at pediatric doses NOT continue beyond attainment of a growth velocity below 2–2.5 cm/year. The decision to discontinue pediatric dosing prior to attainment of this growth velocity should be individualized. ( S , ●●○○ )

Safety Issues of GH Treatment for Patients With GHD

The PES recommends that prospective recipients of GH treatment receive anticipatory guidance regarding the potential adverse effects of intracranial hypertension, slipped capital femoral epiphysis, and scoliosis progression. ( U , )

The PES recommends monitoring of GH recipients for potential development of intracranial hypertension, slipped capital femoral epiphysis, and scoliosis progression by soliciting pertinent history and performing a physical examination at every follow-up clinic visit. Further testing should be pursued if indicated. ( S , ●●●● )

The PES recommends re-assessment of both the adrenal and thyroid axes after initiation of GH therapy in patients whose cause of GHD is associated with possible multiple pituitary hormone deficiencies (MPHD). ( S , ●●○○ )
Technical remark: Evaluate for possible central adrenal and thyroid insufficiencies in those not yet diagnosed, and consider increasing hydrocortisone and/or levothyroxine doses in those already on either of these hormone replacements.

The PES recommends discussion about and monitoring of glucose metabolism of GH recipients who are at increased risk for diabetes due to insulin resistance. ( U , )

The PES recommends counseling prospective recipients of GH treatment regarding the risk of neoplasia. ( U , )

The PES recommends informing at-risk patients about available data and encourages long-term follow up with their oncologist. ( U , )

For children with acquired GHD due to effects of a primary malignancy the PES recommends shared decision-making that involves the patient, family, oncologist, and treating endocrinologist.

Before initiation of GH treatment, the PES recommends sharing with families the most recent data about risks, including the potential effect of GH treatment on the timing of second neoplasm occurrence. ( U , )

For GH initiation after completion of tumor therapy with no evidence of ongoing tumor, a standard waiting period of 12 months to establish "successful therapy" of the primary lesion is reasonable but can also be altered depending on individual patient circumstances. ( U , )
Technical remark: Although many of the intracranial tumors are not “malignant” (i.e., craniopharyngioma), they have the potential to recur. There are no data to suggest treating them differently than malignant tumors with regard to observation periods before initiating GH treatment.

In the rare situation where a child with GHD has an accompanying condition with intrinsic increased risk for malignancy (e.g., Neurofibromatosis-1, Down syndrome, Bloom syndrome, Fanconi anemia, Noonan syndrome, and Diamond-Blackfan anemia), the PES recommends providing counseling regarding the lack of evidence concerning GH effect on malignancy risk in these groups. ( U , )

For children considered not to be at risk, the PES recommends that counseling include information about the unknown long-term (i.e., post-treatment) risks of neoplasia still being studied.

( U , )

The PES recommends that prospective recipients of GH treatment be informed about the uncertainty regarding long-term safety (post-treatment adverse effects in adulthood). ( U , )

Transitional Care After Childhood GH Treatment

The PES recommends that patients with multiple (≥3) pituitary hormone deficiencies regardless of etiology, or GHD with a documented causal genetic mutation or specific pituitary/hypothalamic structural defect except ectopic posterior pituitary, be diagnosed with persistent GHD. ( S , ●●●○ )

The PES recommends re-evaluation of the somatotropic axis for persistent GHD in persons with GHD and deficiency of only one additional pituitary hormone, idiopathic isolated GHD, isolated GHD with or without a small pituitary/ectopic posterior pituitary, and in patients post-irradiation. ( S , ●●●○ )
Technical remark: Testing can be performed after a trial of ≥1 month off GH treatment.

The PES suggests that measurement of the serum IGF-I concentration be the initial test of the somatotropic axis if re-evaluation of the somatotropic axis is clinically indicated. ( C , ●○○○ )

The PES recommends GH provocative testing to evaluate the function of the somatotropic axis in the transition period if indicated by a low IGF-I level. ( S , ●●●○ )

The PES suggests that GH treatment be offered to individuals with persistent GHD in the transition period. There is evidence of benefit. However, the specifics of the patient population that benefits, the optimal time to re-initiate treatment, and the optimal dose are not clear. ( C , ●●○○ )
Technical remark: The transition period is the time from late puberty to establishment of adult muscle and bone composition, and encompasses attainment of adult height.

GH Treatment of Patients With Idiopathic Short Stature (ISS)

In the U.S.A., for children who meet FDA criteria, the PES suggests a shared decision-making approach to pursuing GH treatment for a child with ISS. The decision can be made on a case-by-case basis after assessment of physical and psychological burdens, and discussion of risks and benefits. The PES recommends against the routine use of GH in every child with height standard deviation score (SDS) < -2.25. ( C , ●●●○ )
Technical remark: While studies have shown GH treatment increases the mean height of treated cohorts, there is marked inter-individual variability in responses including some individuals who do not respond to treatment.

The PES suggests a follow-up assessment of benefit in height SDS and psychosocial impact 12 months after GH initiation and dose optimization. ( C , ●●○○ )

Because there is overlap in response between dosing groups, the PES suggests initiating GH at a dose of 0.24 mg/kg/week, with some patients requiring up to 0.47 mg/kg/week. ( C , ●●○○ )

IGF-I Treatment of Patients With Primary IGF-I Deficiency (PIGFD)

The PES recommends the use of IGF-I therapy to increase height in patients with severe PIGFD. ( S , ●●●○ )

Given the absence of a single “best” test that predicts responsiveness to GH treatment, the PES suggests basing the diagnosis of PIGFD/GH insensitivity syndrome (GHIS) on a combination of factors that fall into 4 stages: ( C , ●●●○ )
  1. Screening: auxological parameters and low IGF-I concentration.
  2. Causes of secondary IGF-I deficiency must be excluded, including under-nutrition, hepatic disease, and GHD.
  3. Circulating levels of GH-binding protein (GHBP): very low or undetectable levels suggest Laron syndrome/GHIS while normal levels are non-informative.
  4. IGF-I generation test and mutation analyses can be helpful but have limitations.

The PES recommends a trial of GH therapy before initiating IGF-I for patients with unexplained IGF-I deficiency. Patients with hormone signaling defects known to be unresponsive to GH treatment can start directly on IGF-I replacement. These include patients with very low or undetectable levels of GHBP and/or proven GHThe PES recommends a trial of GH therapy before initiating IGF-I for patients with unexplained IGF-I deficiency. Patients with hormone signaling defects known to be unresponsive to GH treatment can start directly on IGF-I replacement. These include patients with very low or undetectable levels of GHBP and/or proven GH receptor (GHR) gene mutations known to be associated with Laron syndrome/GHIS, GH-neutralizing antibodies, STAT5b gene mutations, and IGF1 gene deletion or mutation. ( S , ●●○○ )

The PES suggests an IGF-I dose of 80–120 μg/kg bid. Similar short-term outcomes were seen with 80 and 120 mcg, but published studies had limitations and there is no strong evidence supporting superiority of one dose over the other. ( C , ●●○○ )
Technical remark: Outside of the U.S.A., IGF-I is also used at 150–180 μg/kg once daily.

The PES recommends administration of IGF-I 20 minutes after a carbohydrate-containing meal or snack, and education of patients/families on the symptoms and risk of hypoglycemia associated with IGF-I treatment. ( S , ●●●● )

General Recommendations

The PES recommends that physicians with expertise in managing endocrine disorders in children manage or provide consultation for the evaluation for GHD-ISS-PIGFD and treatment thereof. ( U , )

The PES recommends further study of the unresolved issues highlighted in these guidelines. ( U , )

Recommendation Grading




Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-like Growth Factor-I Deficiency

Authoring Organization

Publication Month/Year

January 1, 2017

Last Updated Month/Year

September 13, 2023

Supplemental Implementation Tools

Document Type


External Publication Status


Country of Publication


Document Objectives

To update the guidelines published in 2003 on the use of growth hormone (GH). Because idiopathic short stature (ISS) remains a controversial indication, and diagnostic challenges often blur the distinction between ISS, GH deficiency (GHD), and primary IGF-I deficiency (PIGFD), we focused on these three diagnoses, thereby adding recombinant IGF-I therapy to the GH guidelines for the first time.

Target Patient Population

Patients with Idiopathic short stature, GH deficiency, or primary IGF-I deficiency

Inclusion Criteria

Female, Male, Adolescent, Child, Infant

Health Care Settings

Ambulatory, Childcare center, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant


Counseling, Assessment and screening, Diagnosis, Management, Treatment

Diseases/Conditions (MeSH)

D013006 - Growth Hormone, D006130 - Growth Disorders, D018970 - Insulin-Like Growth Factor Binding Protein 1, D019382 - Human Growth Hormone


growth hormone deficiency, growth hormone (GH), insulin-like growth factor-1 (IGF-1)