Growth Hormone Research Paper

Background/Aims: On behalf of the Drug and Therapeutics, and Ethics Committees of the Pediatric Endocrine Society, we sought 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. Methods: This guideline was developed following the GRADE approach (Grading of Recommendations, Assessment, Development, and Evaluation). Results: This guideline provides recommendations for the clinical management of children and adolescents with growth failure from GHD, ISS, or PIGFD using the best available evidence. Conclusion: The taskforce suggests that the recommendations be applied in clinical practice with consideration of the evolving literature and the risks and benefits to each individual patient. In many instances, careful review highlights areas that need further research.

© 2016 S. Karger AG, Basel


In the decade since the publication of the last guidelines for the use of growth hormone (GH) by the Drug and Therapeutics Committee of the Pediatric Endocrine Society (PES; formerly named in honor of Lawson Wilkins) [1], both the field and the approach to guidelines have changed considerably. This report serves to update the 2003 guidelines by following the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group [2]. The large number of approved indications for GH treatment is too unwieldy to review in this manner in a single document. 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 in this guidelines statement. Thus, we have added recombinant IGF-I therapy to the GH guidelines for the first time.

In 1985, GHD became the first indication for recombinant human GH approved by the US Food and Drug Administration (FDA), which it described as “the treatment of pediatric patients who have growth failure due to inadequate secretion of endogenous GH.” In 2003, the FDA expanded GH use to the treatment of ISS, also called non-GH-deficient short stature, defined by height standard deviation score (SDS) ≤-2.25 (≤1.2nd percentile) and associated with growth rates unlikely to permit attainment of adult height (AH) in the normal range, in pediatric patients for whom diagnostic evaluation excludes other causes of short stature that should be observed or treated by other means. The height cutoff of -2.25 SD (1.2nd percentile) corresponds in adults to 160 cm (63 inches) for men and 150 cm (59 inches) for women [3]. The FDA approved IGF-I treatment in 2005 for the long-term treatment of growth failure in pediatric patients with severe PIGFD (defined as both height and serum IGF-I concentration below -3 SD despite normal or elevated GH levels) or with GH gene deletion who developed neutralizing antibodies to GH after a trial of GH therapy. The FDA further stipulated that IGF-I is not indicated to treat secondary IGF-I deficiency resulting from GHD, malnutrition, hypothyroidism or other causes; thus, it is not a substitute for GH therapy. The definitions have evolved since the original FDA indications, with the most recent iteration provided by the International Classification of Pediatric Endocrine Diagnoses (ICPED) [4].

These guidelines provide recommendations for the clinical management of children and adolescents with growth failure due to GHD, ISS, or PIGFD by systematically reviewing the published evidence regarding various practices. In many instances, careful review revealed a paucity of evidence and highlighted areas that need further research. The lack of studies of sufficient quality in support of a practice is not the same as evidence against the practice; until such studies can be performed, individualization of clinical care remains the central tenet of therapy.

Summary of Recommendations

1. Efficacy of GH Treatment for GHD

1.1. We recommend the use of GH to normalize AH and avoid extreme shortness in children and adolescents with GHD. (Strong recommendation, ⚫⚫⚫⚫)

1.2. We suggest against routine cardiac testing, dual X-ray absorptiometry (DXA) scanning, and measurement of lipid profiles in children and adolescents treated with GH. (Conditional recommendation, ⚫⚫⚪⚪)

2. Consideration and Diagnosis of GHD

2.1. Conditions where GH provocative testing is not required to diagnose GHD.

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.

2.1.1. We suggest 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. (Conditional recommendation, ⚫⚫⚪⚪)

2.1.2. We suggest 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). (Conditional recommendation, ⚫⚫⚪⚪)

Technical Remark: A low GH concentration at the time of spontaneous hypoglycemia is alone insufficient to diagnose GHD.

2.2. GH provocative testing.

2.2.1. We recommend against reliance on GH provocative test results as the sole diagnostic criterion of GHD. (Strong recommendation, ⚫⚫⚫⚫)

Technical Remark: 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.

Technical Remark: 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.

Technical Remark: 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.

2.2.2. Given the large discrepancies between GH assays, we recommend 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 published commutability standards. (Strong recommendation, ⚫⚫⚫⚫)

2.2.3. We suggest sex steroid priming prior to provocative GH testing in prepubertal boys older than 11 and in prepubertal girls older than 10 years with AH 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. (Conditional recommendation, ⚫⚫⚪⚪)

Technical Remark: Best available evidence exists for boys; evidence is extrapolated to girls.

Technical Remark: 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 2 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).

Technical Remark: This recommendation applies to GH-naïve patients; it does not retroactively apply to patients already on GH treatment.

2.3. Measurement of spontaneous GH secretion.

2.3.1. We recommend against the use of spontaneous GH secretion in the diagnosis of GHD in a clinical setting. (Strong recommendation, ⚫⚫⚪⚪)

3. Dosing of GH Treatment for Patients with GHD

3.1. We recommend the use of weight-based or body surface area (BSA)-based GH dosing in children with GHD. (Strong recommendation, ⚫⚫⚫⚪)

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

3.2. We recommend an initial GH dose of 0.16-0.24 mg/kg/week (22-35 µg/kg/day) with individualization of subsequent dosing. (Strong recommendation, ⚫⚫⚪⚪)

Technical Remark: Some patients may require higher doses.

3.3. We suggest measurement of serum IGF-I levels as a tool to monitor adherence and IGF-I production in response to GH dose changes. We suggest 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. (Conditional recommendation, ⚫⚪⚪⚪)

3.4. During puberty, we recommend against the routine increase in GH dose to 0.7 mg/kg/week in every child with GHD. (Strong recommendation, ⚫⚫⚪⚪)

3.5. We recommend 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. (Strong recommendation, ⚫⚫⚪⚪)

4. Safety Issues of GH Treatment for Patients with GHD

4.1. We recommend that prospective recipients of GH treatment receive anticipatory guidance regarding the potential adverse effects of intracranial hypertension, slipped capital femoral epiphysis (SCFE), and scoliosis progression. (Ungraded good practice statement)

4.2. We recommend monitoring of GH recipients for potential development of intracranial hypertension, SCFE, 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. (Strong recommendation, ⚫⚫⚫⚫)

4.3. We recommend 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). (Strong recommendation, ⚫⚫⚪⚪)

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 these hormone replacement(s).

4.4. We recommend discussion about and monitoring of glucose metabolism of GH recipients who are at increased risk for diabetes due to insulin resistance. (Ungraded good practice statement)

4.5. Counseling prospective recipients of GH treatment regarding the risk of neoplasia.

4.5.1. We recommend informing at-risk patients about available data and encourage long-term follow-up with their oncologist. (Ungraded good practice statement)

4.5.1.1. For children with acquired GHD due to effects of a primary malignancy:

4.5.1.1.1. We recommend shared decision-making that involves the patient, family, oncologist, and treating endocrinologist. Before initiation of GH treatment, we recommend sharing with families the most recent data about risks, including the potential effect of GH treatment on the timing of second neoplasm occurrence. (Ungraded good practice statement)

4.5.1.1.2. 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. (Ungraded good practice statement)

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.

4.5.1.2. 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), we recommend providing counseling regarding the lack of evidence concerning GH effect on malignancy risk in these groups. (Ungraded good practice statement)

4.5.2. For children considered not to be at risk, we recommend that counseling includes information about the unknown long-term (i.e., posttreatment) risks of neoplasia still being studied. (Ungraded good practice statement)

4.6. We recommend that prospective recipients of GH treatment be informed about the uncertainty regarding long-term safety (posttreatment adverse effects in adulthood). (Ungraded good practice statement)

5. Transitional Care after Childhood GH Treatment

5.1. We recommend 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. (Strong recommendation, ⚫⚫⚫⚪)

5.2. We recommend re-evaluation of the somatotropic axis for persistent GHD in persons with GHD and deficiency of only one additional pituitary hormone, idiopathic isolated GHD (IGHD), IGHD with or without a small pituitary/ectopic posterior pituitary, and in patients after irradiation. (Strong recommendation, ⚫⚫⚫⚪)

Technical Remark: Testing can be performed after a trial of at least 1 month off GH treatment.

5.2.1. We suggest 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. (Conditional recommendation, ⚫⚪⚪⚪)

5.2.2. We recommend GH provocative testing to evaluate the function of the somatotropic axis in the transition period if indicated by a low IGF-I level. (Strong recommendation, ⚫⚫⚫⚪)

5.3. We suggest 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. (Conditional recommendation, ⚫⚫⚪⚪)

Technical Remark: The transition period is the time from late puberty to establishment of adult muscle and bone composition, and encompasses attainment of AH.

6. GH Treatment of Patients with ISS

6.1. In the USA, for children who meet FDA criteria, we suggest 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. We recommend against the routine use of GH in every child with height SDS (HtSDS) ≤-2.25. (Conditional recommendation, ⚫⚫⚫⚪)

Technical Remark: While studies have shown GH treatment increases the mean height of treated cohorts, there is marked interindividual variability in responses, including some individuals who do not respond to treatment.

6.2. We suggest a follow-up assessment of benefit in HtSDS and psychosocial impact 12 months after GH initiation and dose optimization. (Conditional recommendation, ⚫⚫⚪⚪)

6.3. Because there is overlap in response between dosing groups, we suggest initiating GH at a dose of 0.24 mg/kg/week, with some patients requiring up to 0.47 mg/kg/week. (Conditional recommendation, ⚫⚫⚪⚪)

7. IGF-I Treatment of Patients with PIGFD

7.1. We recommend the use of IGF-I therapy to increase height in patients with severe PIGFD. (Strong recommendation, ⚫⚫⚫⚫)

7.2. Given the absence of a single “best” test that predicts responsiveness to GH treatment, we suggest basing the diagnosis of PIGFD/GH insensitivity syndrome (GHIS) on a combination of factors that fall into 4 stages: (Conditional recommendation, ⚫⚫⚫⚪)

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 noninformative

4 IGF-I generation test and mutation analyses can be helpful, but have limitations

7.3. We recommend 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. (Strong recommendation, ⚫⚫⚪⚪)

7.4. We suggest an IGF-I dose of 80-120 µg/kg b.i.d. Similar short-term outcomes were seen with 80 and 120 μg, but published studies had limitations and there is no strong evidence supporting superiority of one dose over the other. (Conditional recommendation, ⚫⚫⚪⚪)

Technical Remark: Outside of the USA, IGF-I is also used at 150-180 µg/kg once daily.

7.5. We recommend administration of IGF-I 20 min after a carbohydrate-containing meal or snack, and education of patients/families on the symptoms and risk of hypoglycemia associated with IGF-I treatment. (Strong recommendation, ⚫⚫⚫⚫)

8. General Recommendations

8.1. We recommend that physicians with expertise in managing endocrine disorders in children manage or provide consultation for the evaluation for GHD-ISS-PIGFD and treatment thereof. (Ungraded good practice statement)

8.2. We recommend further study of the unresolved issues highlighted in these guidelines. (Ungraded good practice statement)

Methods

Taskforce Members

The guidelines taskforce was comprised of 7 pediatric endocrinologists from USA and Canada, and a pediatric bioethicist. The PES Board of Directors approved the appointment of each taskforce member following the society's conflict of interest review policy (available from the PES administrative offices) prior to project commencement. Completed conflict disclosure forms are available through Degnon Associates Inc., the management firm for PES. PES provided funding for a 1-day meeting attended by all taskforce members in Washington, DC, in May 2013; PES members (i.e., the endocrinologists) were reimbursed the cost of one night's hotel stay, while the bioethicist was reimbursed for hotel plus travel expenses, and all were provided lunch during the meeting. Most of the work was accomplished via regular conference calls and e-mail. Taskforce members received no other remuneration for their work on the guidelines, from either PES or any commercial entities. A member of the GRADE group served as consultant, via telephone for the 1-day meeting, and throughout the writing process.

Literature Review and Grading of the Evidence

A series of key questions pertaining to the clinical management of patients with GHD-ISS-PIGFD was drafted and revised until approved by the PES Board of Directors. A medical informationalist from the Johns Hopkins School of Medicine was recruited to assist with appropriate search term generation, comprehensive database queries, and reference management. PubMed, Embase, and the Cochrane Library databases were queried using the terms “growth hormone”, “insulin-like growth factor-I,” their synonyms, and their trade names with the following limits: English language, humans, all child 0-18 years, and published 1985-present. Taskforce members created comprehensive lists of synonymous search terms to capture all studies germane to the key questions. The query excluded studies of pituitary-derived GH due to their poor external validity for clinicians today. A total of ∼15,000 citations were retrieved and a web-based database of the resultant references was generated (RefWorks-COS, Bethesda, MD, USA). Approximately 6,300 citations were specific to GHD or PIGFD.

Each key question was assigned a primary and secondary reviewer, who performed a two-stage review. The primary reviewers sorted the citations collected for their key questions for further inclusion or exclusion by judging the topic relevance according to title and abstract. Abstracts excluded by the primary reviewers were re-reviewed by the secondary reviewers to ensure that all appropriate studies were included. In the second stage, the primary reviewers distilled the study design and results of the full papers into evidence review spreadsheets, including their assessment of the applicability and risk of bias of the individual studies. The secondary reviewers then added comments to the primary reviewers' spreadsheets, independently rating the internal and external validity of each paper. Additional pertinent studies that were found in the bibliographies of the reviewed papers, but had been inadvertently omitted in the database, were pulled and similarly reviewed. ClinicalTrials.gov was also searched for ongoing studies that may have affected consideration of the evidence, and FDA adverse event reports supplemented the safety data.

The 2 reviewers graded the totality of evidence and determined the recommendation for the key question according to the GRADE system [2]. In brief, the quality of the evidence was judged as very low (⚫⚪⚪⚪), low (⚫⚫⚪⚪), moderate (⚫⚫⚫⚪), or high (⚫⚫⚫⚫), reflecting the reviewers' assessment of the quality of the evidence according to GRADE guidelines. Recommendations were assessed as strong (denoted by “We recommend”) or conditional (denoted by “We suggest”). In accordance with GRADE guidelines, strong recommendations reflect confidence that providing such care will afford patients, on balance, more good than harm, while conditional recommendations require more individualized consideration of the risk-benefit assessment for a given patient. On occasion, the taskforce made statements that are marked as “ungraded good practice statements.” These are recommendations without direct supporting evidence that are usually noncontestable and are important to include in the guideline to emphasize certain aspects of care such as providing counseling and education to patients [5].

At the in-person taskforce meeting, each primary reviewer presented the recommendation and evidence grade for the key question with a summary of the supporting evidence. Discussion ensued until the taskforce achieved consensus, defined as at least 6 of the 8 members agreeing on the recommendation as strong or weak. Notes were kept of each discussion, such that major dissenting opinion(s) could be included in the guidelines, which were written based on the results of the taskforce meeting. Further deliberation occurred after the attended meeting via phone conferences and email to determine the final recommendations.

Guiding Principles

Prior to review of the published evidence, the taskforce created a set of guiding principles to standardize the approach across individual reviewers that was approved by all reviewers. AH was selected as the primary outcome in considerations of efficacy. In the absence of data on AH, surrogate short-term outcomes such as growth velocity, change in height z-score, or change in predicted height were considered, but did not form the basis of a recommendation. This is because the short-term outcomes are dynamic and do not reliably predict AH for many children; wide individual variability exists within the heterogeneous treatment population, and outcomes such as change in predicted AH vary markedly depending on the methodology used [6]. To compare AH data across studies for GHD, the parameter (AH SDS - midparental height [MPH] SDS) was used or calculated from available data. The formula for MPH SDS calculation varied among studies. Therefore, the MPH SDS reported for each study was used. To compare AH data across studies for ISS, the parameter (AH SDS minus baseline HtSDS) was used because of the heterogeneity of the populations (familial short stature and nonfamilial short stature). (AH SDS - MPH SDS) was not used for ISS, because MPH may not reflect genetic potential if one or both of the parents has an undiagnosed condition. Studies utilizing predicted AH were excluded, because the short-term effect of GH on HtSDS, especially in high doses, may overestimate the effect on AH [7].

The taskforce values and preferences were consistent in that harm prevention was the utmost factor in formulating strength of recommendation. As a result, the guidelines describe a conservative approach to treating patients with GHD-ISS-PIGFD, recommending only those practices with supporting evidence of sufficient quality and that minimize potential risks to patients. Recommendations in this document were made using the existing literature; future studies may provide evidence that contradict or support the recommendations. Therefore, the taskforce suggests that the recommendations be applied in clinical practice with consideration of the evolving literature and the risks and benefits to each individual patient.

Evidence Supporting Each of the Recommendations

1. Efficacy of GH Treatment for GHD

1.1. We recommend the use of GH to normalize AH and avoid extreme shortness in children and adolescents with GHD. (Strong recommendation, ⚫⚫⚫⚫)

The primary objectives of GH treatment for patients with GHD are acceleration of growth velocity to promote normalization of growth and stature during childhood and attainment of normal AH appropriate for the child's genetic potential. AH data are available in multiple studies of GH treatment for pediatric GHD including GH postmarketing surveillance registries [8,9,10,11], a population-based registry [12], a cancer survivor registry [13], and clinic/hospital-based case series [14,15,16,17]. Collectively, more than 4,520 patients were treated to AH with a mean HtSDS of approximately -1.0. Patients were treated for a mean duration of 7 years (range 2-15.4 years) using a mean GH dose of 0.25 mg/kg/week (range 0.14-0.7 mg/kg/week). The difference between AH SDS and MPH SDS, which reflects whether a patient has achieved his or her genetic potential, showed a mean difference of -0.4 SD (-2.8 cm) with a range of -0.2 to -0.6 SD (-1.4 to -4.2 cm). In contrast, AH SDS of individuals with untreated idiopathic IGHD had a mean of -4.7, with a range of -3.9 to -6 SD [18].

Analysis of 1,258 patients with GHD from the Pfizer International Growth Study (KIGS) showed that Caucasian patients with IGHD treated with GH achieved a mean AH SDS of -0.8 in males and -1.0 in females [9]. Patients with MPHD achieved a mean AH of -0.7 in males and -1.1 SD in females. [AH SDS - MPH SDS] were -0.2 for IGHD (males) and -0.5 (females); for MPHD -0.4 (males) and -0.8 (females). The mean GH dose was 0.21 mg/kg/week for IGHD and 0.18 mg/kg/week for MPHD. Variables that correlated with total height increment (ΔHtSDS) on multivariate analysis included midparental target height, height gain in the first year, height at the start of GH treatment, duration of GH treatment, the maximum GH peak on provocative testing, presence or absence of MPHD, and birth weight. The variables with highest positive correlation were the MPH SDS and the first-year growth velocity.

In 2,165 patients with idiopathic IGHD from the French population-based registry [12] with a mean chronological age of 13.2 ± 2 years and a mean bone age of 10.6 ± 2.3 years in boys and a mean chronological age of 11.6 ± 1.9 years and a mean bone age of 9.5 ± 2 years in girls, mean height gain was 1.1 ± 0.9 SDS resulting in an average AH of -1.6 SD (girls 154 ± 5 cm and boys 165 ± 6 cm). The AH SDS was 0.4 SD lower than MPH SDS, and the GH dose used was only 0.14 mg/kg/week. Baseline variables that predicted favorable height outcome included younger age at start of GH treatment, greater bone age delay, prepubertal status, and severe GHD. In this cohort, 65% were prepubertal at baseline and 48% had peak GH secretion between 7 and 10 µg/L, raising concern that a significant proportion of patients had constitutional delay of growth and puberty. Sex steroid priming was used in only 2% of patients before GH provocative testing. No data on magnetic resonance imaging (MRI) of the brain and pituitary gland were reported.

The available studies are not controlled and differ in their definition of GHD, with various diagnostic threshold peak GH levels, pharmacological agents employed in the GH provocative tests, and GH assays used. Some included patients who may have had underlying ISS instead of GHD. Registries are limited by the fact that the enrolled population is vastly heterogeneous and limited to those patients who consent to enrollment. AH in idiopathic IGHD depends not only on treatment variables (age at initiation of GH treatment, pubertal delay, peak GH level and GH assay used to define GHD, and GH dose), but also on the criteria used to determine AH and consideration of GH termination. Randomized controlled trials (RCT) of GH would have been unethical, as efficacy of treatment in increasing height of patients with GHD had been shown previously with pituitary GH (data not reviewed here).

1.2. We suggest against routine cardiac testing, DXA scanning, and measurement of lipid profiles in children and adolescents treated with GH. (Conditional recommendation, ⚫⚫⚪⚪)

In addition to increasing linear growth, GH exerts crucial effects on lipid, protein, and glucose metabolism. Adults with GHD have reduced cardiac mass and impaired cardiac performance, unfavorable lipid profiles, increased body fat, reduced fibrinolytic activity, decreased insulin sensitivity, premature atherosclerosis, and impaired glucose tolerance [19,20,21]. Few studies have examined the effects of GH treatment for GHD in growing children and adolescents on cardiac function, lipid metabolism, body composition, adipokines, and peripheral inflammatory markers [22,23].

Short-term studies (5 case-control [22,23] and 1 uncontrolled [24]) involving approximately 120 children with GHD documented a positive effect of GH treatment on left ventricular mass, but data on cardiac performance measured by echocardiography (fractional shortening and left ventricular ejection fraction) and vascular function (intimal media thickness at common carotid arteries) were inconsistent. In the prospective, uncontrolled study of Shulman et al., [24], 10 prepubertal children (mean age 5.7 ± 2.7 years; 5 IGHD/5 MPHD (7 with abnormal pituitary gland on MRI and 3 idiopathic) had reduced left ventricular mass that significantly increased after 1 year of GH treatment without any changes in cardiac function, findings similar to those reported by Metwalley et al. [25] and Salerno et al. [26,27]. In the follow-up by Salerno's group, a 2-year prospective case-control study involving 30 prepubertal children with GHD (27 IGHD and 3 MPHD) compared to healthy children matched by age, sex, BSA, and BMI, reduced left ventricular mass normalized after the first year of GH treatment and improvement in left ventricular mass positively correlated with the increase in IGF-I levels [26]. Left ventricular systolic and diastolic function did not change after 2 years of treatment. However, in another study, subtle alterations in left ventricular systolic function were noted [28].

Data on bone density and body composition in children with GHD are generally more consistent. Using DXA, children with untreated GHD showed decreased bone mineral density, decreased lean mass, and increased fat mass, while GH treatment improved these abnormalities in multiple studies [29,30,31]. In a 6-year prospective study of 59 children with GHD, lumbar spine bone mineral density, total body bone mineral density, and body composition were measured using DXA [31]. Mean lumbar spine and total body bone mineral densities were reduced at diagnosis and normalized after 1 year of GH treatment; percentage of body fat was increased at baseline and normalized within 6 months. The severity of GHD or presence of other pituitary hormone deficiencies (IGHD vs. MPHD) was not associated with bone mineral density at diagnosis or with response to GH therapy. In contrast, a study of 5 years of GH treatment found a significant increase in lumbar spine bone mineral density z-score in 35 children with IGHD, but not in 15 children with MPHD [32]. The cohort of patients with MPHD in the first study predominantly had acquired GHD mainly due to intracerebral tumors while the latter cohort of MPHD patients was mostly due to congenital pituitary abnormalities. Thus, the duration of GHD, presence of gonadotropin deficiency, and/or inadequacy of sex steroid replacement may explain the difference between their findings.

Data on lipid profiles in children with untreated GHD compared to healthy controls and the effect of GH treatment are inconsistent. Most of these studies involved small cohorts of children, between 12 and 158 patients. Some studies reported unhealthy lipid profiles in untreated GHD compared to healthy controls, which improved with GH treatment [22,25,33,34,35]. In contrast, other studies reported normal lipid profiles compared to healthy controls, but GH treatment led to significant reduction in total and LDL cholesterol levels and in atherogenic indices [26,28,31,36].

Differences in results in the above studies can be attributed to the following factors: severity of GHD (severe defined as peak GH level on provocative testing of either <3 or <5 µg/L vs. partial GHD with peak GH level between 5 and 10 µg/L); IGHD versus MPHD; different GH assays used to define GHD (polyclonal radioimmunoassay vs. immunometric assays); different GH dosages used; and different durations of GH treatment.

2. Consideration and Diagnosis of GHD

2.1. Conditions where GH provocative testing is not required to diagnose GHD.

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.

2.1.1. We suggest 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. (Conditional recommendation, ⚫⚫⚪⚪)

2.1.2. We suggest 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). (Conditional recommendation, ⚫⚫⚪⚪)

Technical Remark: A low GH concentration at the time of spontaneous hypoglycemia is alone insufficient to diagnose GHD.

“Classical” GHD, as described by Lawson Wilkins refers to the complete or near-complete inability to secrete GH, resulting in extremely slow growth velocity and AH many standard deviations below the mean [37]. In classical GHD, GH treatment restores normal growth, with catch-up to a percentile compatible with MPH, including the upper percentiles of adult stature. In the majority of cases, classical GHD is associated with hypothalamic-pituitary abnormalities on imaging [38], MPHD, or a history of insult to the area such as tumor, surgery, and/or cranial irradiation [39]. In observational studies of these children, provocative tests show GH concentrations very distinct from the normal range such that test precision, reproducibility, and assay performance may not be crucial barriers to precise diagnosis. For example, in a study of 63 treated patients with GHD, all 15 with imaging abnormalities achieved a peak GH concentration below 5 μg/L [38]. Additionally, in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS), the median peak GH level was 2.7 μg/L for the 1,071 subjects with GHD plus any imaging abnormality [39]. In KIGS (Pfizer International Growth Study Database), mean GH peak was 3.1 μg/L in children with imaging abnormalities (excluding pituitary hypoplasia) versus 4.9 μg/L for pituitary hypoplasia and 6.6 μg/L for idiopathic GHD [40]. These tests were not validated as a basis for intervention in an RCT, but observational studies tend to show that very low peak GH response correlates with dramatic response to GH treatment [41,42,43].

Normal neonates have relative hypersomatotropism, with random GH levels higher than older children and adults in the first 5-7 days of life [44,45] and falling in subsequent weeks [46]. Newborns with congenital GHD associated with panhypopituitarism have a greater incidence of hypoglycemia; of 44 patients with congenital GHD, none of the neonates with IGHD had hypoglycemia, while 60-70% of neonates with panhypopituitarism (with or without abnormalities on imaging) experienced hypoglycemia [47]. Neonatal cholestasis with hypoglycemia occurs in panhypopituitarism and improves with replacement of pituitary hormones including GH [48]. A GH level (whether random or associated with spontaneous hypoglycemia) that distinguishes infants with GHD from those with GH sufficiency has not been established definitively. A retrospective study using a validated assay on dried filter-paper blood spots, found that in 314 newborns less than 5 days old, the median GH concentration was 16.4 μg/L with 95% confidence interval of 7-39.4 μg/L. In contrast, 9 newborns with MPHD had GH levels of 5.5 μg/L or less on the same GH assay but samples were collected from these babies between 5 and 28 days of age [44]. Because of GH assay variability, a GH value of ≤5 μg/L in the first week of life in a neonate with deficiency of other pituitary hormones who experiences hypoglycemia is likely sufficient to accurately diagnose GHD. Beyond the first week of life, there are no clear GH threshold levels that discern normal newborns from those with GHD. Beyond the neonatal period, a low GH concentration at the time of hypoglycemia is alone insufficient to diagnose GHD due to low specificity [49]. The challenges in defining normal GH and IGF-I levels in the first 18 months of life are reviewed elsewhere [50].

2.2. GH provocative testing.

2.2.1. We recommend against reliance on GH provocative test results as the sole diagnostic criterion of GHD. (Strong recommendation, ⚫⚫⚫⚫)

Technical Remark: 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.

Technical Remark: 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.

Technical Remark: GH responses to provocative testing are blunted in obese or overweight individuals, and the peak values decrease with increasing BMI. Unlike adults, obesity-dependent modifications to diagnostic criteria in children are undetermined.

Defining growth failure conceptually implies abnormally low growth velocity, while the definition of inadequate GH secretion must be based on more complex evidence. Many cases of GHD are not accompanied by other hypophyseal hormone deficiencies or known hypothalamic-pituitary pathology (idiopathic GHD) and must be diagnosed by measuring GH levels (other GH-related endpoints, e.g. body composition and IGF-I levels, have insufficient sensitivity and specificity to clearly distinguish children with or without GHD). This is further complicated by the pulsatile nature of GH secretion that necessitates the use of provocative (stimulation) testing.

There are no randomized controlled studies to AH that correlate GH provocative testing results with subsequent GH treatment effects on AH. Available evidence is derived from response to treatment in the first few years and consistently shows some predictive value of peaks <10 µg/L on gain in AH SDS [51,52,53]. However, there is no controlled, evidence-based gold standard for this cutoff, which was adopted for identifying partial cases in the continuum between complete deficiency and normal. By modern immunometric methods and standards, 10 μg/L is just below the mean response obtained to most provocative tests in normally growing children, whose 5th percentile lies below 5 μg/L for most tests [54,55].

In the absence of evidence from controlled studies, postmarketing surveys might help estimate how levels within this continuum predict response to treatment. Data from KIGS were mathematically modeled from 593 GH-treated prepubertal children diagnosed as having GHD on the basis of a GH response <10 µg/L [56]. Adding peak GH response to a model of auxological parameters increased the percentage of variance explained from 45 to 60%, making it a statistically significant, but rather modest predictor. However, when individual values for the improvement in first-year height velocity prediction attributable to the GH peak were plotted, the prediction came from peak levels <5 μg/L; at this level, the GH peak increased the prediction by as much as 4 cm of growth in the first year. Similar results were shown in 236 prepubertal children enrolled in the NCGS study in the USA [57]. First-year increase in HtSDS (ΔHtSDS) was indistinguishable between children with peak GH responses 5-10 or >10 μg/L, and ΔHtSDS >1.5 SD was seen only with GH peaks <5 μg/L. The specificity of the cutoff of 10 μg/L was estimated at only 25%. In 1,192 children enrolled in the ICGS study in Japan [58] (also industry-sponsored), a larger ΔHtSDS was seen in children with GH peaks <5 μg/L on two tests, compared to those with at least one test with a peak >5 μg/L. AH analyses from the postmarketing studies are not available and would not be meaningful because of a strong bias to continue treatment only in good early responders.

In addition to lack of AH-based evidence supporting a diagnostically meaningful threshold test result, there are several limitations to comparing peak GH responses across provocative tests. We could find no evidence indicating that peak GH values are similar using different provocative agents. Using the same analytical assay to measure peak GH concentrations of 68 normally growing children, Zadik et al. [54] found good agreement between insulin- and arginine-stimulated GH peaks (14.2 ± 6.3 vs. 13.1 ± 6.1 μg/L), but clonidine, another widely used stimulus, gave much higher levels (21.0 ± 10.7 μg/L). In this study of normally growing children, 1 SD below the mean for peak GH value was at or below 10 µg/L, with the 5th percentile being less than half of this cutoff. These results were corroborated in a large, registry-based study of 3,233 cases in France [59], in which correlation coefficients (r) between GH peaks on two tests in the same patient ranged from 0.35 to 0.6, meaning that the r2 (expressing the fraction of the total variance explained by the fact that the two tests were performed on the same subject) ranged from 12 to 36%. These results also suggested imperfect reproducibility of the same test in the same patient, with the highest correlation, that being for duplicate testing with insulin stimulation, having a coefficient of only 0.72 (r2 = 52%).

Studies show that GH response to provocative testing depends on BMI and that GH response to stimulation is considerably lower in obese children [60,61]. In a prospective study of 65 normally growing obese children, spontaneous GH secretion was less than half of reference, and it normalized after weight loss [62]. There is insufficient evidence for establishing BMI-corrected cutoffs for GH provocative testing in children. A retrospective cross-sectional study of glucagon stimulation testing in adults with BMI ≥25 proposed lowering the diagnostic threshold from the standard 3 μg/L (failed by 45% of the 47 healthy adults studied) to 1 μg/L (failed by 6% of healthy controls, 59% of 41 adults with partial pituitary deficiency, and 90% of the 20 adults with total pituitary deficiency studied) [63]. For the obese child with poor growth, other endocrinopathies (e.g., hypothyroidism and hypercortisolism) should be excluded before testing for GHD, as these conditions, if present and untreated, can cause falsely low GH levels upon GH provocative testing.

2.2.2. Given the large discrepancies between GH assays, we recommend 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 published commutability standards. (Strong recommendation, ⚫⚫⚫⚫)

Serum GH concentrations are currently measured using a variety of methods against a variety of standards. Normal values were established using polyclonal radioimmunoassays and purified pituitary standards. Currently used immunometric assays with monoclonal antibodies and recombinant standards have higher specificity, but the use of different standards and antibodies with specificities for different GH isoforms has resulted in large discrepancies between assays.

Therefore, standardization or, at least, harmonization is required to meaningfully evaluate and compare results. An important first step in harmonization is the adoption of recombinant primary reference material, the most current and widely used of which is IRP IS 98/574, 22k rhGH isoform, as recommended by the 2006 and 2011 consensus statements [64]. If different methods give the same result for the same serum pools, the assays can be considered standardized. If not, harmonization is achieved by documenting sample-independent differences and deriving correction factors to obtain the same values for the same sample, by the use of commutable serum pools as outlined by Ross et al. [65].

Discrepancies among current GH assays lead to diagnostic misclassifications. Using three reference assays (two using the same standard, 88/624), Hauffa et al. [66] re-examined 699 peak samples from GH provocative testing. The mean difference among assays varied from 5.4 to 10.3 mU/L (2.7 to 5.1 µg/L). Assignment to GHD- versus GH-sufficient groups varied substantially among different assays in a subset of 132 subjects who had had standardized insulin and arginine testing, resulting in misclassification of up to 29% of cases. In another study, samples from 47 provocative tests were assayed with four different methods [67]. Discrepancies were found with significant effects on diagnostic outcome. One immunometric assay classified 36% of tests as indicating GHD compared to 15% for the standard radioimmunoassay.

Several countries have sought to standardize or harmonize their GH assays. A systematic, multi-laboratory effort at standardization of assays in Finland between 1998 and 2003 showed considerable improvement in concordance, but even in the last year of the effort, discrepancies persisted [68]. Another harmonization effort in Germany found a 27% misclassification rate before adjusting results by a conversion factor [69]. In Japan, a systematic effort at harmonization using a uniform biosynthetic standard resulted in lowering of the cutoff from 10 to 6 µg/L due largely to the immunometric methods measuring much lower than the original radioimmunoassay [70].

2.2.3. We suggest sex steroid priming prior to provocative GH testing in prepubertal boys older than 11 and in prepubertal girls older than 10 years with AH 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. (Conditional recommendation, ⚫⚫⚪⚪)

Technical Remark: Best available evidence exists for boys; evidence is extrapolated to girls.

Technical Remark: 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 2 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).

Technical Remark: This recommendation applies to GH-naïve patients; it does not retroactively apply to patients already on GH treatment.

In children with constitutional delay of growth and puberty, the normal decline in prepubertal growth velocity with age (interrupted by the pubertal growth spurt) is prolonged and may lead to frankly abnormal growth velocity [71]. This is accompanied by a reduction in the GH response to provocative stimuli [72], which has led to the supposition that, in prepubertal children of pubertal age, GH testing be preceded by brief treatment with sex steroids.

Sex steroid priming before GH provocative testing in prepubertal children of pubertal age improves diagnostic specificity without compromising the sensitivity of diagnosing severe GHD and can prevent inappropriate GH treatment of children with constitutional delay of growth and puberty. Administration of 1-2 mg of estradiol to 44 children with ISS raised the mean lower 95% confidence interval of peak GH response to a sequential arginine-clonidine test from clearly “abnormal” at 3.7 up to 8.3 µg/L. This very substantial gain in specificity was not accompanied by a loss of sensitivity, as response was unaltered in 15 children with GHD established by the presence of other pituitary defects (7 of the 15 cases), imaging findings, or other phenotypic features [73]. In a longitudinal study of 8 children with delayed puberty, mean peak GH response was 8.2 µg/L, below the GHD cutoff and substantially lower than that seen in control children of prepubertal age. Mean peak response completely normalized to 15.8 µg/L when the children developed puberty 0.83-2.14 years later [72]. Similar results were found in a cross-sectional study of 84 normal, untreated children, where the percentage of those who would have been classified as GHD by the stricter cutoff of 7 µg/L declined from 61% at Tanner stage I to zero at stages IV and V [74]. An observational study reported AH in 50 otherwise healthy boys evaluated for short stature with delayed puberty (mean delay of 2 years) and growth velocity <5 cm/year. These boys had peak GH values in the deficient range without sex steroid priming (mean 4.9-5.4 µg/L ± 2.1-3.0) [75]. With sex steroid priming, mean peak GH values after stimulation were 15.4-19.3 µg/L ± 5.1-5.9 using three different priming doses of testosterone. Untreated, the boys' mean HtSDS changed from -2.4 ± 0.4 (range -4.0 to -1.7) at time of testing to -1.27 ± 0.72 (range -2.54 to +0.49) at AH. The resultant HtSDS was within the normal range and commensurate with the boys' MPH. However, there were no data on females, and most of the boys had a normal AH prediction at the time of testing (mean -1.3 ± 1.0 SD, with range from -3.1 SD to +2 SD).

In generating this statement, the guidelines taskforce placed high value on reducing unnecessary GH treatment of children with constitutional delay of growth and puberty, with its associated potential harms (proven or theoretical), costs, and psychological and physical burden. Sex steroid priming was repeatedly shown to increase the specificity, without hampering the sensitivity, of GH provocative testing for severe GHD, but the studies all involved small sample sizes, and there was only one study reporting AH, the chosen outcome to grade the evidence. This study showed that the boys reached normal AHs without GH treatment, but many had predicted AHs in the normal range at the time of testing. While the range of predicted AHs in this study went down to -3.1 SD, group data can obscure changes at the individual level. There is no direct evidence that patients with predicted AH below -2 SD at the time of testing and classified as GH-deficient solely when tested without sex hormone priming achieve a height within the adult normal range without GH treatment. Hence, the evidence was graded as low. The taskforce reached a unanimous consensus that prepubertal children of pubertal age diagnosed with GHD using sex steroid priming likely will experience greater benefit from GH treatment than such children diagnosed without priming. The possibility remains that, of such patients diagnosed as having GHD solely without sex steroid priming, the patients with abnormally low AH predictions at the time of testing may still require GH treatment to achieve a normal AH.

No gynecomastia in boys or other side effects have been reported with the recommended doses of sex steroid priming. No systematic controlled evidence exists to favor any of the proposed protocols over another. Wetterau [76] summarized the various methods used.

2.3. Measurement of spontaneous GH secretion.

2.3.1. We recommend against the use of spontaneous GH secretion in the diagnosis of GHD in a clinical setting. (Strong recommendation, ⚫⚫⚪⚪)

Given the limitations of provocative testing, the idea of measuring spontaneous secretion as a profile with serial sampling [77] or as an integrated level by continuous withdrawal [78] is attractive. It seems plausible that a child unable to normally secrete GH could still respond to the nonphysiological pharmacology of provocative testing, a condition termed neurosecretory dysfunction [77]. This hypothesis was tested by GH treatment of 7 short children with abnormally low growth velocity, who had provocative responses >10 µg/L but low spontaneous secretion [77]. Short-term acceleration of growth was observed, similar to that seen in children with conventionally defined GHD. Neither long-term growth nor adult-height data were presented. In addition to first-year acceleration of height velocity being a very imperfect predictor of AH gain, a major weakness of this study was that 4 of the 7 patients were of pubertal age with severe bone age delay. Onset of puberty during treatment was not evaluated and could account for much or all of this acceleration. A similar first-year growth acceleration was reported in 2 other studies of children diagnosed by the same criteria [79,80,81], and both of these studies suffered from the same limitations.

We could find a report of the effects on AH in only one retrospective study [80] that showed a mean AH gain of 1.03 SDS following GH treatment in children who met the criteria for neurosecretory dysfunction, compared to untreated ISS cases with normal spontaneous secretion. This gain is virtually identical to that obtained in treated ISS (see discussion below) making the contribution of the spontaneous GH measurement very questionable.

Normative data for spontaneous GH secretion were established by a study that showed that 4/10 normal-height, normally growing children and 8/35 with constitutional delay, but normal growth velocity, had overnight secretory patterns compatible with the diagnosis of neurosecretory GHD [82]. An additional study also found overlap of spontaneous GH secretion between healthy, normally growing children and children with GHD [83]. Unfortunately, results of frequent GH sampling were inconsistent when normal children were studied on two separate occasions under identical conditions [84]. In light of these limitations, the taskforce felt any potential benefit of overnight GH sampling did not warrant the burden to patients and, hence, rated this recommendation strongly.

3. Dosing of GH Treatment for Patients with GHD

For the indication of GHD, manufacturers of somatropin obtained governmental agency approval for dose ranges of 25-35 µg/kg/day or 0.16-0.24 mg/kg/week, as listed in product inserts (so called standard dosing). In the USA, a few manufacturers obtained approval for higher dosing prepubertally (up to 0.3 mg/kg/week or ∼42-50 µg/kg/day depending upon dosing of GH 6 days or 7 days per week) and up to 0.7 mg/kg/week during puberty (pubertal dosing; for GHD only). Dosing based upon BSA is also reported in some product inserts used outside the USA. In this section, doses are reported as mg/kg/week or mg/m2/week. Some studies reported doses in international units (IU). The conversion formula 3.0 IU per 1 mg of GH was used for dose comparison, as most of the studies cited administered authentic rhGH (the conversion formula for methionyl GH, an early GH formulation, is 2.7 IU per 1 mg). Studies reporting doses in mg/m2 were not converted to mg/kg because weight and BSA change at different rates during childhood, thereby precluding a reliable formula for dose conversion. As a point of reference, for a 30-kg, 1-m2 child, 0.16-0.24 mg/kg/week equals 4.8-7.2 mg/m2/week.

3.1. We recommend the use of weight-based or BSA-based GH dosing in children with GHD. (Strong recommendation, ⚫⚫⚫⚪)

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

Studies demonstrating the positive effects of GH on achieved AH have overwhelmingly used weight- or BSA-based dosing [8,9,10,11,12,13,14,15,16,17,85,86,87,88]. Selection of dosing based upon weight or BSA seems to be a matter of personal or national preference [89]. The rationale for using BSA-based dosing draws upon the supposition that drug metabolism does not decrease proportionally to increases in body weight, as it is mainly dependent on extracellular fluid volume, which is weight-independent. Differences in dose calculations between the weight- and BSA-based approaches are most prominent at younger ages and with obesity. Hughes et al. [90] noted that older children receive a lower total GH dose if BSA dosing is used, rather than weight-based dosing. Rigorous studies comparing weight-based with BSA-based dosing have not been conducted; thus, there is insufficient evidence to recommend one dosing regimen over the other.

IGF-I-based dosing of GH treatment has been proposed based on two premises. First, there is large interindividual variation in growth response to the same per kg body weight GH dose, so anthropometric-based dosing may not be optimal for a particular patient. Second, because the growth effects of GH are due in large part to its induction of IGF-I, serum IGF-I concentration can serve as a biomarker of GH action in an individual patient and allow more individualized dose titration, akin to dosing levothyroxine based on thyroid function tests. Cohen et al. [91] evaluated the efficacy of serum IGF-I-based dosing on growth after 2 years of GH therapy in a randomized trial. Children diagnosed with GHD who received GH doses that achieved a serum IGF-I SDS of +2 experienced a statistically significant greater difference in HtSDS (+2.04 ± 0.17 from pretreatment HtSDS) than children randomized to receive GH to achieve a serum IGF-I SDS of 0 (+1.41 ± 0.13 from pretreatment HtSDS). The average GH dose to achieve an IGF-I SDS of +2 was 91 µg/kg/day (median 65 µg/kg/day), while the average GH dose to achieve a serum IGF-I SDS of 0 was 37 µg/kg/day (median 33 µg/kg/day). Within each treatment group, a wide range of doses was needed to achieve the target IGF-I level. With an IGF-I target of +2 SDS, fewer than 65% of children required GH doses above 50 µg/kg/day, while 35% required GH doses of 50 µg/kg/day (∼0.35 mg/kg/week) or less. In the IGF-I target of 0 SDS group, fewer than 20% of children required GH doses above 50 µg/kg/day. Thus, some children with GHD experience a more robust rise in IGF-I level (correlated with linear growth) than others on similar weight-based doses [92]. Studies comparing the effectiveness of IGF-I-based dosing with that of standard weight-based dosing on AH have not yet been done. As the panel elected to base recommendations on AH outcomes, there is insufficient evidence at this time to recommend IGF-I-based dosing over weight- or BSA-based dosing.

Thrice weekly (TIW) dosing of GH was used initially after introduction of recombinant GH as a holdover from dosing paradigms used with pituitary-derived GH. Daily dosing of GH resulted in higher absolute height gain and gain in HtSDS than dividing the same weekly dose as TIW in 1-4 years of comparison study [93,94]. In the studies reporting AH in GH-treated children, dosing of GH was 6-7 days per week in the majority of studies, or a mixture of TIW or more frequent dosing in the remaining. As the bulk of AH data were obtained in persons who received dosing more often than TIW, TIW dosing is not suggested.

3.2. We recommend an initial GH dose of 0.16-0.24 mg/kg/week (22-35 µg/kg/day) with individualization of subsequent dosing. (Strong recommendation, ⚫⚫⚪⚪)

Technical Remark: Some patients may require higher doses.

The strength of the evidence indicating a difference in AH between children with GHD who receive different doses of GH is moderate-low as studies differ in their conclusions. Given the burden of GH treatment on the health-care system and the unresolved long-term risks of treatment, the lowest dose with demonstrated efficacy should be used.

The body of evidence concerning the effect of different GH dosing regimens on AH outcomes is of moderate-to-low quality. This evidence consists of reports of mean GH doses used in registry- or population-based studies, analyses of potential variables that may affect AH in patients enrolled in registries, and nonrandomized or randomized trials with low patient numbers. Early data from the NCGS and KIGS registries, which included data with higher weekly doses of recombinant GH (0.18-0.3 mg/kg/week) than were used in pituitary-derived GH studies [95,96], indicated that mean AH SDS-MPH SDS was -0.5 SD with ∼0.18 mg/kg/week [10] or -0.5 SD with 0.3 mg/kg/week [11], suggesting that the higher weekly dose of recombinant GH could result in larger height gains over the lower weekly dose that had been used with pituitary-derived GH. Later data with a greater number of enrolled subjects in the French national registry (n = 1,524), Pharmacia/Pfizer registry (n = 1,258), and a Dutch cohort (n = 552), did not find a significant correlation between GH dose and AH on multivariate analysis [9,12,97]. Participants in these studies were treated for 4-9 years, and the reported mean GH doses were 0.18-0.24 mg/kg/week with a range between 0.11 and 0.28 mg/kg/week. In a Canadian cohort of 96 patients, a fixed dose of 0.18 mg/kg/week given for an average of 9 years resulted in heights that were within -0.5 SD from MPH [15]. A retrospective case-control study of 26 patients who received 0.15 or 0.3 mg/kg/week found that the 13 patients who received the 0.3 mg/kg/week GH dose achieved a mean AH SDS - MPH SDS 0.73 SD higher than patients who received the lower dose [14]. The participants had similar MPH, baseline height, and treatment duration. An RCT of 35 subjects compared AH in children receiving 0.7 mg/m2/day (4.9 mg/m2/week) versus 1.4 mg/m2/day (9.8 mg/m2/week) [98]. The mean AH SDS - MPH SDS was -0.7 versus -0.3 SD in the low and high dose groups, respectively, a difference of 4 cm that did not reach statistical significance. This study may have been insufficiently powered to detect a difference, so larger controlled trials may yet demonstrate a statistically significant effect of higher GH doses. In summary, in studies reporting AH, the majority of patients were administered GH doses between 0.18 and 0.24 mg/kg/week and multivariate analysis of the data did not consistently reveal a correlation between higher dosing and greater AH. Studies directly comparing different dose regimens enrolled small numbers of patients and results differed between studies.

As one of its guiding principles, the guidelines taskforce endorses harm prevention (theoretical or proven) over practices that have unproven benefits. High dosing of GH carries a higher risk of long-term adverse effects theoretically and a certain higher cost burden on health-care systems. Since the body of evidence is conflicting on the comparative effectiveness of different GH doses on AH, the panel elected to recommend initiation of GH at the lower dose range.

Interindividual variability in growth velocity after initiation of GH, likely reflecting heterogeneity of populations diagnosed with GHD, suggests that subsequent dosing should be individualized. Variables such as first-year growth velocity, height at start, duration of treatment, peak GH concentration during provocative testing, and MPH have been correlated with a taller AH [9,12]. In efforts to predict individual response to GH from pretreatment characteristics and short-term treatment outcomes, models have been developed using data from registries [7,56,99,100]. Models have been verified retrospectively in two different cohorts of less than 100 children [56]. One study compared growth of children with GHD randomized to receive standard weight-based GH dosing or individualized GH dosing modeled from pretreatment characteristics [101]. After 2 years of treatment, the HtSDS - MPH SDS was similar between the groups (-0.42 ± 0.46 vs. -0.48 ± 0.67), but the individualized GH dose group had a narrower distribution of SDS (range of 2.25 in the individualized group vs. 3.36 in the standard dose group). In other studies, short-term growth endpoints, such as 1- and 2-year growth velocity and change in HtSDS, have been shown to be increased by factors such as higher GH dosing or dose titration to IGF-I levels [92,102]. Although logical and promising, these strategies to optimize growth parameters in the short term have not been tested to AH. Additionally, the comparative effectiveness of these various strategies has not been tested. Thus, a statement on the most effective strategy to individualize GH dosing after GH initiation (using anthropometric parameters, modeled GH responsiveness, and/or IGF-I levels) cannot be surmised from the available data.

3.3. We suggest measurement of serum IGF-I levels as a tool to monitor. adherence and IGF-I production in response to GH dose changes. We suggest 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. (Conditional recommendation, ⚫⚪⚪⚪)

GH stimulates the synthesis and secretion of IGF-I, whose circulating concentration generally increases with increased GH dose. Thus, serum IGF-I concentration is a useful biomarker of GH exposure both in diagnosis and in treatment monitoring [102]. The target IGF-I level that results in optimal growth while minimizing future theoretical risk is not known. Meta-analysis of cohort and case-control studies in the general non-GH-treated population indicates that serum IGF-I levels in both the low and high ends of the normal range are associated with greater cancer and all-cause mortality [103]. The studies used for the meta-analysis measured IGF-I levels in subjects of various ages from 20 to 98 years, with the majority between ages 40-90 years and the duration of follow-up ranging between 5 and 18 years. The long-term effects of briefer periods of higher IGF-I levels in childhood are not known.

The long-term risks of higher IGF-I levels of short or long duration are not resolved. The consensus panel endorses harm prevention in the treatment of children with GH. As long as the potential risk is unresolved, we suggest that the serum IGF-I concentration be monitored on a regular basis with the goal to keep IGF-I levels in the normal range for age and pubertal status. Assays used to quantify IGF-I include immunometric and liquid chromatography/tandem mass spectroscopy techniques. Available commercial assays may provide different IGF-I values when applied to the same serum sample [104]. For that reason, when making clinical decisions for an individual, the IGF-I values must be interpreted against the gender-, age-, and puberty-specific reference ranges provided by the commercial laboratory used in measuring that value. Levels of IGF-binding protein 3 (IGFBP-3) and acid-labile subunit have also been associated inconsistently with risk of certain cancers, and modulate the bioavailability of IGF-I. However, the complex interactions among the three proteins have not been studied sufficiently to support using alternative markers (e.g., molar ratio of IGF-I/IGFBP-3 as an estimation of free IGF-I) to predict long-term risks [105,106,107].

3.4. During puberty, we recommend against the routine increase in GH dose to 0.7 mg/kg/week in every child with GHD. (Strong recommendation, ⚫⚫⚪⚪)

The FDA approved higher GH dosing during puberty based on results of an RCT [85] in which individuals who received the higher GH dose of 0.7 mg/kg/week during 3 years of puberty had a higher growth velocity and achieved a higher AH SDS. The absolute difference in mean AH between the high dose and control dose (0.3 mg/kg/week) groups was 4.6 cm after 3 years and 5.7 cm after 4 years. Although MPH SDS between the two groups was not different at baseline, AH SDS - MPH SDS was not reported; the effect of therapy experienced by the individual may well be different from the group. The control dose group achieved median IGF-I levels of 615 µg/L (range 139-1,079) whereas the high dose group achieved IGF-I levels of 910 µg/L (range 251-1,843) after 36 months of therapy. Of the 97 subjects enrolled, 10 experienced serious adverse events, 4 in the standard dose group and 6 in the high dose group. Four of the 48 patients receiving the higher dose experienced effects consistent with GH excess, such as enlarging shoe size, ankle swelling, and hip pain. Although no cases of intracranial hypertension or slipped capped femoral epiphysis were reported, the study was not adequately powered to detect these potential serious side effects.

Randomized studies comparing pubertal doses lower than 0.7 mg/kg/week to standard dosing have also been performed [108,109,110]. Ninety-two Swedish children were randomized to standard dosing (0.1 IU/kg/day, ∼33 µg/kg/day) or pubertal dosing once or twice daily (0.2 IU/kg/day, ∼67 µg/kg/day) at Tanner stage 2 [109]. Median AH SDS - MPH SDS was between 0 and 1 SD for all groups with a similar distribution of data. Another study randomized 49 adolescents to standard dosing (0.7 mg/m2/day) or pubertal dosing (1.4 mg/m2/day) at Tanner stage 2 [110]. Mean AH SDS - MPH SDS (0.1) was not different between groups. Using data from the KIGS database, multiple linear regression analysis revealed that gender, age at puberty onset, and height at puberty onset were associated more strongly with pubertal growth than was GH dose [111].

Members of the consensus panel unanimously agreed that the high rate of observed effects consistent with GH excess and the untested potential for more adverse effects in a greater sample size carried an undesirable risk of harm to patients receiving the 0.7 mg/kg/week dose. This concern, coupled with the unresolved long-term risk of higher dose of GH and health-care cost burden of the 0.7 mg/kg/week dose, prompted the consensus panel to recommend against the routine use of this dose during puberty.

In 1513, the Spanish explorer Juan Ponce de Len arrived in Florida to search for the fountain of youth. If he got any benefit from his quest, it was due to the exercise involved in the search.

Few men today believe in miraculous waters, but many, it seems, believe in the syringe of youth. Instead of drinking rejuvenating waters, they inject human growth hormone to slow the tick of the clock. Some are motivated by the claims of the "anti-aging" movement, others by the examples of young athletes seeking a competitive edge. Like Ponce de Len, the athletes still get the benefit of exercise, while older men may use growth hormone shots as a substitute for working out. But will growth hormone boost performance or slow aging? And is it safe?

Human growth hormone: Up close and personal

Growth hormone (GH) is a small protein that is made by the pituitary gland and secreted into the bloodstream. GH production is controlled by a complex set of hormones produced in the hypothalamus of the brain and in the intestinal tract and pancreas.

The pituitary puts out GH in bursts; levels rise following exercise, trauma, and sleep. Under normal conditions, more GH is produced at night than during the day. This physiology is complex, but at a minimum, it tells us that sporadic blood tests to measure GH levels are meaningless since high and low levels alternate throughout the day. But scientists who carefully measure overall GH production report that it rises during childhood, peaks during puberty, and declines from middle age onward.

GH acts on many tissues throughout the body. In children and adolescents, it stimulates the growth of bone and cartilage. In people of all ages, GH boosts protein production, promotes the utilization of fat, interferes with the action of insulin, and raises blood sugar levels. GH also raises levels of insulin-like growth factor-1 (IGF-1).

Therapeutic use

GH is available as a prescription drug that is administered by injection. GH is indicated for children with GH deficiency and others with very short stature. It is also approved to treat adult GH deficiency — an uncommon condition that almost always develops in conjunction with major problems afflicting the hypothalamus, pituitary gland, or both. The diagnosis of adult GH deficiency depends on special tests that stimulate GH production; simple blood tests are useless at best, misleading at worst.

Adults with bona fide GH deficiencies benefit from GH injections. They enjoy protection from fractures, increased muscle mass, improved exercise capacity and energy, and a reduced risk of future heart disease. But there is a price to pay. Up to 30% of patients experience side effects that include fluid retention, joint and muscle pain, carpal tunnel syndrome (pressure on the nerve in the wrist causing hand pain and numbness), and high blood sugar levels.

GH doping

Adults who are GH deficient get larger muscles, more energy, and improved exercise capacity from replacement therapy. Athletes work hard to build their muscles and enhance performance. Some also turn to GH.

It's not an isolated problem. Despite being banned by the International Olympic Committee, Major League Baseball, the National Football League, and the World Anti-Doping Agency, GH abuse has tainted many sports, including baseball, cycling, and track and field. Competitive athletes who abuse GH risk disqualification and disgrace. What do they gain in return? And do they also risk their health?

Because GH use is banned and athletic performance depends on so many physical, psychological, and competitive factors, scientists have been unable to evaluate GH on the field. But they can conduct randomized clinical trials that administer GH or a placebo to healthy young athletes and then measure body composition, strength, and exercise capacity in the lab.

A team of researchers from California conducted a detailed review of 44 high-quality studies of growth hormone in athletes. The subjects were young (average age 27), lean (average body mass index 24), and physically fit; 85% were male. A total of 303 volunteers received GH injections, while 137 received placebo.

After receiving daily injections for an average of 20 days, the subjects who received GH increased their lean body mass (which reflects muscle mass but can also include fluid mass) by an average of 4.6 pounds. That's a big gain — but it did not translate into improved performance. In fact, GH did not produce measurable increases in either strength or exercise capacity. And the subjects who got GH were more likely to retain fluid and experience fatigue than were the volunteers who got the placebo.

If you were a jock in high school or college, you're likely to wince at the memory of your coach barking "no pain, no gain" to spur you on. Today, athletes who use illegal performance-enhancing drugs risk the pain of disqualification without proof of gain.

GH for aging

Among its many biological effects, GH promotes an increase in muscle mass and a decrease in body fat. As men age, GH levels fall. During the same time span, muscle mass declines and body fat increases. And so, the theory goes, the way to arrest these effects of aging is to inject GH.

Similar claims have been made for other hormones that decline with age, including testosterone and dehydroepiandrosterone (DHEA) in men, and estrogen in women. Research shows that estrogen replacement does more harm than good in older women, and there is no solid evidence that testosterone and DHEA are safe and effective for healthy older men. But that has not stopped the growth of "anti-aging" and "regenerative medicine" clinics and Web sites.

Expensive injections of growth hormone are offered by many practitioners, even though the FDA has not approved the use of GH for anti-aging, body building, or athletic enhancement, and the marketing or distribution of the hormone for any of these purposes is illegal in the U.S. According to one estimate, 20,000 to 30,000 Americans used GH as "anti-aging" therapy in 2004 alone; according to another, 100,000 people received GH without a valid prescription in 2002.

To evaluate the safety and efficacy of GH in healthy older people, a team of researchers reviewed 31 high-quality studies that were completed after 1989. Each of the studies was small, but together they evaluated 220 subjects who received GH and 227 control subjects who did not get the hormone. Two-thirds of the subjects were men; their average age was 69, and the typical volunteer was overweight but not obese.

The dosage of GH varied considerably, and the duration of therapy ranged from two to 52 weeks. Still, the varying doses succeeded in boosting levels of IGF-1, which reflects the level of GH, by 88%.

As compared to the subjects who did not get GH, the treated individuals gained an average of 4.6 pounds of lean body mass, and they shed a similar amount of body fat. There was a slight drop in total cholesterol levels, but no significant changes in LDL ("bad") cholesterol, HDL ("good") cholesterol, triglycerides, aerobic capacity, bone density, or fasting blood sugar and insulin levels. But GH recipients experienced a high rate of side effects, including fluid retention, joint pain, breast enlargement, and carpal tunnel syndrome. The studies were too short to detect any change in the risk of cancer, but other research suggests an increased risk of cancer in general and prostate cancer in particular.

Beat the clock

"Every man desires to live long," wrote Jonathan Swift, "but no man would be old." He was right, but the fountain of youth has proved illusory. And while more study is needed, GH does not appear to be either safe or effective for young athletes or healthy older men. But that doesn't mean you have to sit back and let Father Time peck away at you. Instead, use the time-tested combination of diet and exercise. Aim for a moderate protein intake of about .36 grams per pound of body weight; even big men don't need more than 65 grams (about 2 ounces) a day, though athletes and men recovering from illnesses or surgery might do well with about 20% more. Plan a balanced exercise regimen; aim for at least 30 minutes of moderate exercise, such as walking, a day, and be sure to add strength training two to three times a week to build muscle mass and strength. You'll reduce your risk of many chronic illnesses, enhance your vigor and enjoyment of life, and — it's true — slow the tick of the clock.

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