Archived Policies - Prescription Drugs
Growth Hormone (GH)
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Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, Hayes, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.
This is not an all-inclusive listing of all growth hormone preparations. Refer to the U.S. Food and Drug Administration (FDA) for all labeled indications of those growth hormones not listed on this policy.
ALERT: All self-injectable medications are administered under the pharmacy benefit.
Growth hormone (GH) therapy is addressed by indications, and the following specific criteria are met (see table below), GH therapy may be considered medically necessary when:
• There are FDA approved label indications; or
• The FDA has granted an Orphan Drug Designation to the drug; or
• There is an off-label listing within a standard reference compendium (such as the American Hospital Formulary Service Drug Information [AHFS DI] or the Thompson Micromedex Drug Dex Compendium [Drug Dex]).
MEDICALLY NECESSARY TABLE
If the FDA approved indication is:
Then the criteria for review includes the following for medically necessary consideration:
Growth hormone (GH) deficiency (GHD), in children
• Failed TWO provocative GH stimulation tests, each with peak value < 10 ng/ml. Testing can be done with growth hormone releasing hormone (GHRH), arginine, insulin, L-dopa, clonidine, or glucagon); OR
• Documentation of proven GHD resulting from either 1) a destructive lesion of the pituitary, 2) a medical treatment, including but not limited to ablative pituitary radiation or surgery, 3) central nervous system pathology; 4) genetic defect (Refer to Turner’s syndrome, Prader-Willi syndrome, or Noonan’s syndrome below); or 5) trauma.
Supportive documentation for children with GHD:
• Documentation of growth velocity under 5.0 cm/year with documentation of height at least 2.0 standard deviations (SD) below mean over one year or more or more than 1.5 SDs sustained over two years; and
• Bone age as determined by standard x-ray techniques to be two years or more behind chronological age.
NOTE 1: In children, GH therapy is typically discontinued when the growth velocity is less than 2.0 cm/year; when epiphyseal fusion has occurred; or when the height reaches the 5th percentile of adult height.
NOTE 2: Once GHD has been established in childhood no further documentation of need is required through age 18.
Short-stature, in children
• Height less than 3rd percentile for chronological age with chronic renal insufficiency, with serum creatinine greater than 1.5 mg/dL, or a creatinine clearance less than or equal to 75 ml/minute per 1.73 m2; OR
• As a result of proven SHOX (short-stature homeobox-containing gene) deficiency.
NOTE 3: In pediatric patients with chronic renal failure undergoing transplantation, GH therapy is discontinued at the time of transplant or when the growth velocity is less than 2 cm per year, when epiphyseal fusion has occurred, or when the height reaches the 5th percentile of adult height.
GHD, in adults
• Failed TWO provocative GH stimulation tests, each with peak value < 5 ng/ml. Testing can be done with insulin and one of the GHRH preparations, arginine, L-dopa, clonidine, or glucagon; OR
• Documentation of proven GHD resulting from either:
1) A destructive lesion of the pituitary;
2) A medical treatment, including but not limited to ablative pituitary radiation or surgery;
3) Central nervous system pathology;
4) Genetic defect;
5) Low concentration of insulin-like growth factor-1 (IGF-1); or
NOTE 4: Insulin Provocation is the preferred test for confirming GHD in most adults. It must be ONE of the TWO tests provided for documentation of GHD unless the test is contraindicated because the patient has history of seizures, coronary artery disease, or high risk of coronary artery disease.
NOTE 5: A provocation test using arginine and GHRH is also acceptable and is considered more stringent than tests using arginine alone or L-dopa alone.
NOTE 6: Although an abnormal GH response has been traditionally defined as less than 10 ng/mL, different tests have different potencies, and the cutoff is likely to be lower when using monoclonal-based GH assays and rhGH reference preparations.
NOTE 7: Only about 25% of children with documented GHD will be found to have GHD when tested as adults. Therefore, once adult height has been achieved, they should be re-tested ONE time as adults to determine if continuing GH replacement therapy is medically necessary.
NOTE 8: When a diagnosis of GHD is established for an adult, and therapy with GH is initiated, documentation may be requested at one to two year intervals to demonstrate that the patient is obtaining measurable clinical benefit from GH therapy.
NOTE 9: A physician should consider a trial of withdrawal of GH therapy for patients who do not have demonstrated clinical benefit.
Acquired immunodeficiency syndrome (AIDS) wasting
• Weight loss greater than 10% of baseline weight (refer to NOTE below) that cannot be explained by a concurrent illness other than human immunodeficiency virus (HIV) infection; AND
• Patient is on concurrent antiviral medications.
NOTE 10: GH therapy is discontinued when the loss is less than 10% of baseline weight loss.
Associated growth failure.
Associated growth failure.
Associated growth failure.
Severe burns, in children
• 3rd degree burns to prevent growth delay, when the treatment begins during acute hospitalization; AND
• Up to one year after the 3rd degree burn, because scar tissue may interfere with growth.
Severe burns, in adults
3rd degree burns requiring promotion of wound healing.
Short bowel syndrome
Treatment with specialized nutritional support in conjunction with optimal management of short bowel syndrome, including dietary adjustments, enteral feedings, parenteral nutrition, and fluid and micronutrient supplements.
NOTE 11: For additional discussion of short bowel syndrome, see Medical Policy MED201.021, Intestinal Rehabilitation Therapy.
All label and off-label uses of any FDA approved drugs not included in the above medical necessity table are considered not medically necessary OR experimental, investigational and/or unproven as outlined in the tables below when:
• The FDA has determined its use to be contraindicated for a specific condition; or
• The off-label uses cannot be validated by standard reference compendia or peer reviewed literature.
NOT MEDICALLY NECESSARY TABLE
If the FDA approved indication is:
Then the explanation for not medically necessary is:
Small for gestational age (SGA)
• Pediatric patients born SGA who fail to show catch up growth by age 2; as there are no established criteria for SGA or catch-up growth (refer to NOTE below).
NOTE 12: Absence of catch-up growth was defined as a height velocity below 1.0 SD, adjusted for age. However, in the data submitted to the FDA as part of the approval process, the mean height of enrolled patients was at least 2 SDs below the mean without documented GHD.
Non-GHD with short-stature (idiopathic short-stature [ISS])
• Pediatric patients who are non-GHD with short-stature (also known as ISS), as studies have failed to demonstrate a significant impact of height on psychosocial morbidity.
NOTE 13: The American Academy of Pediatrics (AAP) has pointed out that there will always be a population of individuals considered short based on the normal distribution of height, regardless of how the bell-shaped curve may be altered by GH therapy. The American Association of Clinical Endocrinologists and the Growth Hormone Research Society have defined “short-stature” as a height more than 2 SDs below the mean for age and sex. The FDA-approved indication is for children with a height SD of -2.25 below the mean. Using this proposed definition, approximately 1.2% of all children would be defined as having ISS.
• Patients with partial GHD, as these patients do not meet the criteria required for GHD.
• Further lab testing of children without classic GHD to diagnose partial GHD, or other abnormalities of GH secretion or bioactivity, is considered not medically necessary.
NOTE 14: This includes overnight hospitalization of children for testing of spontaneous GH secretion.
Neurosecretory GH dysfunction
• Patients with neurosecretory GH dysfunction, as these patients do not meet the criteria required for GHD.
• Further lab testing of children without classic GHD to diagnose partial GHD, or other abnormalities of GH secretion or bioactivity, is considered not medically necessary.
NOTE 15: This includes overnight hospitalization of children for testing of spontaneous GH secretion.
Experimental, Investigational and/or Unproven Table
All Other Indications
Experimental, investigational and/or unproven indications for GH therapy include, but are not limited to, the following:
• Constitutional delay (lower than expected growth percentiles compared with their target height percentiles and delayed skeletal maturation when growth velocities and rates of bone age advancement are normal);
• In conjunction with gonadotropin releasing hormone (GnRH) analogues as a treatment of precocious puberty;
• GH therapy in older adults to counter the effects of aging (without proven GHD);
• Anabolic therapy (except for AIDS), provided to counteract acute or chronic catabolic illness (e.g., surgery outcomes, trauma, cancer, chronic hemodialysis, chronic infectious disease) producing catabolic (protein wasting) changes in both adult and pediatric patients;
• Anabolic therapy to enhance body mass or strength for professional, recreational, or social reasons;
• Glucocorticoid-induced growth failure;
• Short-stature due to Down’s syndrome;
• Intrauterine growth retardation;
• Treatment of altered body habitus (e.g., buffalo hump, lipodystrophy [fat mal-distribution]) associated with antiviral therapy in HIV infected patients;
• Treatment of obesity;
• Treatment of cystic fibrosis (CF);
• Treatment of idiopathic dilated cardiomyopathy;
• Treatment of juvenile idiopathic- or juvenile chronic-arthritis;
• Treatment of advanced age or symptoms of aging;
• Treatment of inflammatory bowel disease; OR
• Treatment of children with “genetic potential” (i.e., lower than expected height percentile based on parents’ height).
The following diagnostic tests for GHD are considered experimental, investigational and/or unproven:
• 24-hour continuous monitoring of GH levels, OR
• Serum levels of insulin-like growth factor-binding protein (IGFBP).
NOTE 16: Refer to Medical Policy RX501.065 for coverage for Mecasermin Recombinant (Increlex ™ or Iplex/iPLEX ™), which is a recombinant insulin-like human growth factor.
Recombinant human growth hormone (GH) is approved by the U.S. Food and Drug Administration (FDA) for various indications and is also proposed for various off-label indications.
Human GH, also known as somatotropin, is synthesized in somatotropic cells of the anterior lobe of the pituitary gland. GHD can occur due to a variety of conditions, such as:
• Pituitary tumor,
• Pituitary dysfunction due to prior surgery or radiation treatment,
• Extrapituitary tumor,
• Sarcoidosis, and/or other infiltrating disorders, or
GHD in children is manifested primarily by short stature. In adults, as well as in some children, other abnormalities associated with GHD are often evident. They include changes in body composition, higher levels of low-density (LD) lipoprotein cholesterol, lower bone density, and a decreased self-reported quality of life compared with healthy peers. Some evidence has suggested that there may be increases in cardiovascular disease and overall mortality, but it is less clear whether GHD causes these outcomes.
Major points of controversy are what defines “inadequate secretion of normal endogenous growth hormone” and what constitutes “growth failure.” Before the availability of biosynthetic GH, GH was rationed to children with classic GHD, as defined by a subnormal response (<10 ng/mL, approximately, depending on GH assay) to GH provocation tests. However, the ready supply of GH has created interest in expanding its use to short-stature children without classic GHD, often referred to as partial GHD, neurosecretory GH dysfunction, constitutional delay in growth and development, or idiopathic short stature (ISS).
“Classic” GHD is suggested when the abnormal growth velocity (typically <10th percentile) or height is more than 2 standard deviation score (SDS) below the current population mean, in conjunction with a chronologic age that is greater than the height age and bone age. Interest in broadening the use of GH to non-GHD children has resulted in GH evaluation in many children who are simply below the 3rd percentile in height, with or without an abnormal growth velocity.
These broadened patient selection criteria have remained controversial due to uncertainties in almost every step in the diagnosis and treatment process as outlined below:
• Selection of patients to be tested,
• Limitations in the laboratory testing for GH,
• Establishment of diagnostic cutoffs for normal versus abnormal GH levels,
• Availability of the laboratory tests to predict response to GH therapy,
• Changes in growth velocity due to GH therapy,
• Whether resulting final height is significantly improved, and
• Whether this improvement is clinically or emotionally significant for the patient.
In addition, there are many ethical considerations regarding GH therapy, most prominently appropriate informed consent when the therapy is primarily requested by parents due to their particular psychosocial concerns regarding height.
Outcome Measures in GH Research
The most common outcome measure reported in GH research is change in height. For some situations, such as in patients with documented GHD or genetic disorder and short stature, improvements in height alone may be a sufficient outcome measure. However, in most situations, a change in height is not in itself sufficient to demonstrate that health outcomes are improved. There is insufficient evidence to establish that short stature is associated with substantial impairments in psychological functioning or quality of life, or that increases in height improve these parameters. Similarly, improvements in other measures of body composition (e.g., muscle mass, muscle strength) are not in themselves sufficient to establish that health outcomes are improved. Therefore, for most conditions in this literature review, changes in other outcome measures, (e.g., functional status, quality of life, disease-specific clinical outcomes) are necessary to demonstrate an improvement in health outcomes.
Beginning in 1985, recombinant human growth hormone (rhGH; E-coli [Escherichia-coli] -derived somatropin or mammalian-cell-derived somatropin) has been marketed for a variety of FDA-labeled indications. Although GH products may differ in specific labeled indications and dosing requirements, clinical evidence may not support differential effectiveness of one product over the other for FDA-approved clinical indications.
In 2001, Genotropin®, a E-coli-derived somatropin, received an FDA-labeled indication for treatment of pediatric patients born small for gestational age (SGA) who failed to show catch-up growth by age 2 years. Most children born SGA normalize their stature during infancy, but about 15% maintain an exceptionally short stature at least throughout childhood. Epidemiologic surveys have suggested that the average adult height of men and women who did not exhibit catch-up growth as children is 5 feet, 6 inches, in men and 5 feet, 1 inch, in women. GH has been investigated in these children, based in part on the hypothesis that a GH resistance is a possible etiology of the growth retardation. In 2003, the FDA approved a rhGH product for use in non-GH-deficient short stature, defined by the manufacturer as a height SDS of -2.25 below the mean. This indication for GH is the first indication based on short stature alone, without an underlying etiology. Additional FDA-labeled indications include treatment of children with Prader-Willi syndrome, Turner syndrome, and ISS. Treatment of adults includes either adult-onset or childhood onset GHD.
As with Genotropin®, Humatrope®, a E-coli-derived somatropin, has been FDA-approved for pediatric patients. Pediatric Patients: Treatment of children with short stature or growth failure associated with growth hormone (GH) deficiency, Turner syndrome, ISS, SHOX (short stature homeobox) deficiency, and failure to catch up in height after SGA birth. The SHOX gene provides instructions for making a protein that regulates the activity of other genes. On the basis of this role, the SHOX protein is called a transcription factor. The SHOX gene is part of a large family of homeobox genes, which act during early embryonic development to control the formation of many body structures. Specifically, the SHOX gene is essential for the development of the skeleton. It plays a particularly important role in the growth and maturation of bones in the arms and legs. Humatrope® has been FDA-approved for adult patients as a treatment for childhood-onset or adult-onset GHD.
Somatropin (Norditropin Nordiflex®):
Beginning in 2000, Norditropin®, a E-coli-derived somatropin, had been FDA-approved and was indicated for the long-term treatment of children who have growth failure due to inadequate secretion of endogenous growth hormone. Currently, the FDA-labeled indications include treatment of children with growth failure due to growth hormone deficiency (GHD), short stature associated with Noonan syndrome, short stature associated with Turner syndrome and short stature born SGA with no catch-up growth by age 2 to 4 years. For adult, treatment with either adult-onset or childhood onset GHD has been FDA-approved.
Nutropin®, a E-coli-derived somatropin, has been FDA-approved for adult patients as a treatment for childhood-onset or adult-onset GHD. In addition to treatment of children with growth failure due to GHD, ISS, and Turner syndrome, Nutropin has been FDA-approved for treatment of chronic kidney disease (CKD) up to the time of renal transplantation in pediatric patients. The Nutropin® label states that children with growth failure secondary to CKD should be examined periodically for evidence of progression of renal osteodystrophy. Slipped capital femoral epiphysis (SCFE) or avascular necrosis of the femoral head may be seen in children with advanced renal osteodystrophy, and it is uncertain whether these problems are affected by somatropin therapy. X-rays of the hip may be obtained prior to initiating somatropin therapy in CKD patients, providers and parents should be alert to the development of a limp or complaints of hip or knee pain in these children treated with Nutropin®. No studies have been completed evaluating Nutropin® therapy in patients who have received renal transplants.
The FDA-approved labeled indications for Omnitrope®, a E-coli-derived somatropin, are as follows for children: treatment of children with growth failure due to GHD, Prader-Willi Syndrome, SGA, Turner syndrome, and ISS. Treatment of adults includes either adult-onset or childhood onset GHD. The initial approval in 2006 included the requirement that GHD should be confirmed by an appropriate growth hormone stimulation test. Additionally, use of Omnitrope® would be used as long-term treatment.
Saizen®, a E-coli-derived somatropin, has 2 FDA-approved indications, for the treatment of children with growth failure due to GHD and treatment of adults with either adult onset or childhood onset of GHD.
Serostim®, a mammalian-cell-derived somatropin, is indicated for the treatment of HIV patients with wasting or cachexia (wasting syndrome) to increase lean body mass and body weight, and improve physical endurance. Patients having cachexia or wasting, experience loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite when the patient is not actively trying to lose weight that cannot be reversed nutritionally.
The FDA-approved labeled indication for Tev-Tropin®, a E-coli-derived somatropin, includes only 1 condition, for the treatment of children who have growth failure due to GHD. The utilization for adults is not included on the label. The studies used for FDA-approval did not include treatment of adults. In regards to geriatric use, the safety and effectiveness of Tev-Tropin in patients aged 65 and over has not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of somatropin, and may be more prone to develop adverse reactions.
The FDA-approved label for Valtropin®, a E-coli-derived somatropin, has not been changed since the April 2007 release for sale of Valtropin® and is specific to the criteria for some of the indications and confirmation of diagnosis testing. Valtropin® is indicated for the treatment of pediatric patients who have growth failure due to inadequate secretion of endogenous GH, for the treatment of growth failure associated with Turner syndrome in patients who have open epiphyses. For adult patients, Valtropin® is indicated for replacement of endogenous growth hormone in patients with GHD who meet either of the following criteria:
1. Adult Onset: Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
2. Childhood Onset: Patients who were GHD during childhood as a result of congenital, genetic, acquired, or idiopathic causes.
The Valtropin® FDA-approved label states the following, “In general, confirmation of the diagnosis of adult growth hormone deficiency in both groups usually requires an appropriate growth hormone stimulation test. However, confirmatory growth hormone stimulation testing may not be required in patients with congenital/genetic growth hormone deficiency or multiple pituitary hormone deficiencies due to organic disease.”
Zorbtive™, a mammalian-cell-derived somatropin, is indicated for the treatment of short bowel syndrome in patients receiving specialized nutritional support. It is recommended that Zorbtive™ therapy be used in conjunction with optimal management of short bowel syndrome. Specialized nutritional support may consist of a high carbohydrate, low-fat diet, adjusted for individual patient requirements and preferences.
This policy was created in 1990 based on the U.S. Food and Drug Administration (FDA) –approved labeled indications and routinely updated with literature searches, particularly for off-label use, with the most recent update including searches in the MedLine database and standard reference compendiums through February 2017. The following discussion focuses on the most controversial aspects of growth hormone (GH) use.
Safety of GH Treatment
Adverse effects (AEs) can occur with GH treatment. In children, increased rates of skeletal problems (e.g., worsening of scoliosis) can occur in association with a rapid growth spurt. In adults, arthralgias, edema, and carpal tunnel syndrome are common. Less common AEs include pancreatitis and gynecomastia. (1, 2) There is also concern that GH treatment may increase the rate of malignancy, particularly de novo leukemia, in patients without risk factors. However, to date, there is insufficient evidence of a causative relation between GH treatment and malignancy rates.
Several publications on the safety of GH therapy have used French registry data and vital statistics. A 2012 analysis of long-term mortality after GH treatment was conducted by Carel et al. (3) A total of 6928 children were included in the study. Indications for GH therapy included idiopathic isolated growth hormone deficiency (GHD; n=5162), neurosecretory dysfunction (n=534), idiopathic short stature (ISS) (n=871), and born small for gestational age (SGA) (n=335). The mean dose of GH used was 25 μg/kg/d and the mean treatment duration was 3.9 years. Patients were followed for a mean of 17.3 years. As of September 2009, follow-up data on vital status were available for 6558 (94.7%) of participants. Ninety-three (1.42%) of the 6558 individuals had died. The mortality rate was significantly higher in patients treated with GH than would be expected on the basis of year, sex, or age (standardized mortality ratio, 1.33; 95% confidence interval [CI], 1.08 to 1.64). Examination of the causes of death found a significant increase in mortality due to circulatory system diseases. In addition, there was a significant increase in the number of deaths due to bone tumors (3 observed deaths versus 0.6 expected deaths) but no other types of cancers or overall cancer deaths. There was also a significant increase in the number of deaths due to cerebral or subarachnoid hemorrhage (4 observed deaths versus 0.6 expected).
In 2014, Poidvin et al. reported on the same data, focusing on risk of stroke in adulthood among childhood users of GH therapy. (4) This analysis included 6874 children with idiopathic isolated GHD or short stature; mean length of follow-up was 17.4 years. There were 11 (0.16%) validated cases of stroke and the mean age at the time of stroke was 24 years. Risk of stroke was significantly higher in adults who had used GH than in general population controls. Stroke risk was also compared with general population controls. Standard incidence ratios were 2.2 (95% CI, 1.3 to 3.6) compared with registry data from Dijon and 5.3 (95% CI, 3.0 to 8.5) using Oxford registry data. The increased risk was largely for hemorrhagic stroke (8/11 cases), and this elevated risk persisted when the 3 patients who had been small for gestational age were excluded from the analysis. In all of the analyses from this research team, there were a small number of events (i.e., deaths or stroke), and thus conclusions from these data are not definitive on the long-term safety of GH therapy.
According to the drug prescribing information, GH therapy use has been associated with sudden death in children with Prader-Willi syndrome. (64) These deaths occurred among children who were severely obese or had severe respiratory impairment; these markers are now considered contraindications to GH treatment use.
Growth Hormone Deficiency (GHD)
GHD in Children
In children with GHD, treatment has been found to increase growth velocity and final height. Root et al. followed approximately 20,000 children for 9 years as part of the National Cooperative Growth Study. (5) Growth velocity improved compared with pretreatment values, and this improvement was maintained for at least 4 years. For children treated for at least 7 years, improvements in the mean height standard deviation score (SDS) ranged from 1.3 to 2.5, depending on the specific underlying condition. If treatment is started at an early age, most children can achieve a final height close to that expected from parental height. In a study of 1258 patients in the Pfizer International Growth Database, the standard deviation (SD) for differences between the final height achieved and the midrange of predicted height from parental values ranged between -0.6 and +0.2, depending on the specific underlying condition. (6)
GHD in Adults
In adults with GHD, evidence from randomized controlled trials (RCTs) has shown that treatment leads to increases in lean body mass and decreases in body fat. (7) Meta-analyses of RCTs have shown evidence for increases in muscle strength and exercise capacity, although these findings were not robust across all studies. (8, 9) There is also evidence from meta-analyses that GH therapy is associated with increased bone mineral density (BMD) in adults with GHD. (10, 11) For example, a 2014 meta-analysis by Barake et al. identified 9 placebo-controlled RCTs with at least 1-year follow-up on the effect of daily GH therapy on BMD. (11) Analysis of RCT data found a statistically significant increase in BMD of the lumbar spine and femoral neck in patients with GHD who received GH therapy for more than 2 months. Change in BMD ranged from 1% to 5% at the spine and 0.6% to 4% at the femoral neck. A limitation of the Barake analysis is that data were not available on fracture rates, a clinically important outcome. The evidence on other outcomes, such as quality of life, lipid profiles, cardiovascular disease, and total mortality, is inconsistent and insufficient to determine whether these outcomes are improved with treatment. (12-15)
Section Summary: Growth Hormone Deficiency
Large cohort studies, RCTs, and meta-analyses have found that, for patients with documented GHD and clinical manifestations such as short stature, GH replacement has improved growth velocity and final height achieved. In addition, studies have shown that GH therapy can ameliorate the secondary manifestations of GHD such as increase in lean muscle mass and BMD seen primarily in older children and adults.
Short Stature due to Prader-Willi Syndrome
Most children with Prader-Willi syndrome have hypothalamic dysfunction and are GH-deficient. The value of testing for GHD before treatment in these patients is questionable. None of the clinical studies selected patients for treatment based on presence or absence of GHD, nor were results reported separately for those with or without GHD. Information from the product label indicates that the height SDS for Prader-Willi syndrome children in the clinical studies was -1.6 or less (height was in the 10th percentile or lower).
Several RCTs in children have shown improvements in health outcomes with GH treatment. For example, a 2008 RCT published by Festen et al. included 42 infants and 49 prepubertal children (age range, 3-14 years). (16) GHD status was not part of the study eligibility criteria. The study found that GH treatment significantly improved height, body mass index, head circumference, and body composition. In 2012, the same investigators published cognitive outcomes in children participating in this trial. (17) During the 2-year randomized study, mean total IQ score and subtests did not change significantly from baseline in GH-treated children. In untreated children, there was no significant change in total IQ score, but scores on 2 of 3 subtests significantly declined from baseline.
Moreover, a 2013 RCT found that the addition of GH therapy to physical training resulted in greater improvements in motor development than physical training alone. (18) This 2-year, single-blind trial included 22 children newly diagnosed with Prader-Willi syndrome (mean age, 12.9 months). GHD status was not considered in the study eligibility criteria. Outcomes were evaluated every 3 months and multiple regression analysis was conducted to evaluate whether GH had an impact on motor development over time. Among the results was a finding that GH had statistically significant interaction effects for a model predicting motor development age using the Alberta Infant Motor Scale.
Lo et al. (2015) conducted a 2-year RCT of GH therapy versus no treatment and followed children on GH therapy for an additional 6 years. (19) The trial included 42 prepubertal children (age range, 3.5-14 years); children were not selected based on GHD status. The primary outcome was the impact of GH treatment on behavior, measured by 2 validated parent questionnaires: the Developmental Behavior Checklist (DBC) and the Children’s Social Behavior Questionnaire (CSBQ). At the end of the 2-year RCT, there were no significant differences in DBC and CSBQ scores between the GH-treated and no-treatment groups. Findings were similar at the end of the 8-year follow-up period.
Section Summary: Short Stature due to Prader-Willi Syndrome
Several RCTs have found improvement in height and other outcomes (e.g., motor development) in children with Prader-Willi syndrome. One study did not find a significant change in problem behavior after GH treatment. Studies have found increased risk of adverse events in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment and thus these are contraindications.
Short Stature due to Chronic Renal Insufficiency
In 2013, Wu et al. published a meta-analysis of RCTs evaluating the impact of GH therapy on height outcomes following renal transplant in children ages 0 to 18 years. (20) Five trials (total N=401 participants) met reviewers’ inclusion criteria (RCTs including renal allograft recipients between 0 and 18 years old). Trials were published between 1996 and 2002. A meta-analysis found significantly improved height velocity at the end of a year in children taking GH compared with a no-treatment control group. At the beginning of the year, both groups had a negative height SDS, with no statistically significant differences between groups. After 1 year, the pooled mean difference (MD) in height SDS was 0.68 (95% CI, 0.25 to 1.11; p=0.002) in favor of the GH group. There were no statistically significant differences between groups in the rate of rejection episodes or in renal function.
Previously, in 2012, Hodson et al. published a Cochrane review of RCTs evaluating GH treatment in children with chronic kidney disease. (21) To be included in the review, trials needed to include children 18 years old or younger who were diagnosed with chronic kidney disease and were predialysis, on dialysis, or posttransplant. In addition, trials had to compare GH treatment with placebo, no treatment, or a different GH regimen, and needed to include height outcomes. Seven RCTs with 809 children met reviewers’ criteria. Study entry criteria varied (e.g., ranging from <3rd percentile for chronologic age to <50th percentile for chronologic age). Overall, treatment with GH (28 IU/m2/wk) compared with placebo or no specific therapy resulted in a statistically significant increase in height SDS at 1 year (8 studies; MD=0.82; 95% CI, 0.56 to 1.07). Moreover, a pooled analysis of 7 studies found a significant increase in height velocity at 1 year in the group receiving GH treatment compared with control (MD=3.88 cm/y; 95% CI, 3.32 to 4.44 cm/y).
An example of an individual RCT is Hokken-Koelega et al., conducted in the Netherlands. (22) This double-blind, placebo-controlled crossover trial included 20 prepubertal children with severe growth retardation and chronic renal failure. Entry criteria included height velocity less than the 25% percentile for chronologic age. Patients received 6 months of subcutaneous injection of GH (4 IU/m2/d) before or after 6 months of placebo injection. There was a 2.9 cm greater increase in height velocity per 6 months with GH than with placebo. Long-term follow-up data on children in this and other Dutch RCTs (maximum of 8 years of treatment) were published in 2000. (23) GH treatment resulted in significant improvement in the height SDS compared with baseline scores (p<0.001). Moreover, the mean height SDS reached the lower end (-2 SDS) of the normal growth chart after 3 years of treatment. Puberty began at a median age within the normal range for girls and boys, and GH therapy did not significantly affect parathyroid hormone concentrations, and there were no radiologic signs of renal osteodystrophy.
Section Summary: Short Stature due to Chronic Renal Insufficiency
Numerous RCTs and systematic reviews of these RCTs have found significantly increased height and height velocity in children with short stature associated with chronic renal insufficiency who were treated with GH therapy compared with another intervention. There were no significant increases in adverse events related to renal function.
Short Stature due to Turner Syndrome
Short stature is almost universal in Turner syndrome, although the syndrome is not associated with GHD. Poor growth is evident in utero and further deceleration occurs during childhood and at adolescence. The mean adult height for those with Turner syndrome is 58 inches (4 feet, 10 inches). FDA approvals for GH were based on the results of RCTs that included final adult height as the outcome. For example, a group of patients with Turner syndrome given somatropin (Humatrope®) at a dosage of 0.3 mg/kg/wk for a median of 4.7 years achieved a final height of 146.0±6.2 cm (57.5±2.25 in) compared with an untreated control group who achieved a final height of 142.1±4.8 cm (56±2 in). (64)
In 2007, a Cochrane review identified 4 RCTs (total N=365 patients) evaluating GH for treating Turner syndrome. (24) Studies included children who had not yet achieved final height, had treated children for at least 6 months, and compared GH with placebo or no treatment. Only 1 trial reported final height, so outcomes could not be pooled. A pooled analysis of 2 trials found that short-term growth velocity was greater in treated than in untreated children (MD=3 cm/y; 95% CI, 2 to 4 cm/y).
Section Summary: Short Stature due to Turner Syndrome
Several RCTs have been published and/or are reported in FDA documents. Studies have found that GH therapy increases height outcomes (e.g., final height, height velocity) in children with short stature due to Turner syndrome compared with placebo or no treatment.
Short Stature due to Noonan Syndrome
Noonan syndrome is associated with slow growth, starting in early childhood. In 2015, Giacomozzi et al. published a systematic review of literature on the effect of GH therapy on adult height. (25) Included in the review were studies treating individuals with a diagnosis of Noonan syndrome with no other causes of short stature and a normal karyotype in females. In addition, studies needed to follow patients for at least 3 years. Twenty-three studies met the inclusion criteria; none were RCTs and only 1 was controlled. Three studies were case reports and the remainder prospective or retrospective cohort studies. In the 1 controlled study (MacFarlane et al. ), over the 3-year follow-up, the GH-treated group gained a mean of 3.3 cm more than the untreated group. Among the uncontrolled studies, 2 reported adult height. Mean height SDS was -2.8 (SD=0.6) and mean adult height SDS was -1.4 (SD=0.9). Two uncontrolled studies reported near-adult height, which was -2.1 (SD=0.9). In addition, 2 studies reported a change in height SDS corresponding to 8.6 cm (SD=5.9). The data were limited by the paucity of controlled studies and lack of RCTs.
Section Summary: Short Stature due to Noonan Syndrome
There are a number of studies; however, few included comparator interventions. A systematic review of the literature found that GH therapy was associated with an increase in height in patients with short stature due to Noonan syndrome.
Short Stature due to Short Stature Homeobox-Containing Gene Deficiency
A 2010 Health Technology Assessment on GH treatment of growth disorders in children identified 1 RCT evaluating GH therapy for children with short stature due to short stature homeobox-containing gene deficiency (SHOX). (27) This industry-sponsored, open-label multicenter trial was published by Blum et al. in 2007. (28) It included 52 prepubertal children age at least 3 years who had SHOX deficiency. Height requirements were less than the 3rd percentile of the local reference range or less than 10th percentile with height velocity less than the 25th percentile. Participants were randomized to receive 2 years of GH treatment (n=27) or usual care (n=25). The primary outcome was first-year height velocity. Fifty-one of 52 patients completed the study. The first-year height velocity was 8.7 cm/y (SD=0.3) in the GH therapy group and 5.2 cm/y (SD=0.2) in the usual care group; the difference between groups was statistically significant (p<0.001). Height gain over the 2-year treatment period was 16.4 (SD=0.4) cm in the treatment group and 10.5 (0.4) cm in the usual care group (p<0.001). No serious adverse events were reported for either group.
Section Summary: Short Stature due to Short Stature Homeobox-Containing Gene Deficiency
An RCT found that children with short stature due to SHOX deficiency had significantly greater height velocity and significantly more height gain after 2 years when treated with GH versus no GH treatment.
Treatment of Severe Burns
A 2012 Cochrane systematic review included RCTs evaluating the impact of GH therapy on the healing rates of burn wounds. (29) Thirteen trials were identified that compared GH therapy with another intervention or to placebo. Six included only children and 7 involved only adults. Twelve studies were placebo-controlled. Findings of 2 studies reporting wound healing time in days were pooled. The mean healing time was significantly lower in the GH-treated group than in the placebo group (MD = -9.07 days; 95% CI, -4.39 to -13.76). The reviewers also conducted meta-analyses of studies that did not conduct survival analyses but did follow patients until their wounds healed. These analyses found significantly shorter healing time in patients who received GH therapy among adults (2 studies) and among children (2 studies). A pooled analysis of 5 studies did not find a statistically significant difference in mortality among patients receiving GH therapy and placebo (relative risk [RR], 0.53; 95% CI, 0.22 to 1.29). The mortality analysis likely was underpowered; the total number of deaths was 17. A pooled analysis of 3 studies involving adults found significantly shorter hospital lengths of stay in patients who received GH therapy compared with placebo (MD = -12.55 days; 95% CI, -17.09 to -8.00 days). In another pooled analysis, there was a significantly higher incidence of hyperglycemia in GH-treated patients than in controls (RR=2.65; 95% CI, 1.68 to 4.16).
One RCT measuring mortality included 54 adult burn patients who survived the first 7 postburn days. (30) Those patients showing difficulty with wound healing were treated with recombinant human growth hormone (rhGH) and compared with those healing at the expected rate with standard therapy. Mortality of rhGH-treated patients was 11% compared with 37% for those not receiving rhGH (p=0.027). Infection rates were similar in both groups. Singh et al. studied 2 groups of patients (N=22) with comparable third-degree burns; those who received GH had improved wound healing and lower mortality (8% versus 44%). (31) Another placebo-controlled trial found no benefit to GH with regard to length of hospitalization in 24 adults with severe burns. (32)
Prevention of Growth Delay in Children with Severe Burns
Children with severe burns show significant growth delays for up to 3 years after injury. GH treatment in 72 severely burned children for 1 year after discharge from intensive care resulted in significantly increased height in a placebo-controlled, randomized, double-blinded trial. (33) Aili Low et al. found that GH treatment in severely burned children during hospitalization resulted in significantly greater height velocity during the first 2 years after burn compared with a similar group of untreated children. (34)
Section Summary: Severe Burns
Numerous RCTs evaluating GH for treatment of severe burns have been published. Pooled analyses found significantly shorter healing times and significantly shorter hospital stays with GH therapy versus placebo. Several RCTs have found significantly greater height gains in children with burns who received GH therapy versus placebo or no treatment.
In 2004, Moyle et al. published a systematic review of controlled and uncontrolled studies on selected treatments of HIV wasting. (35) To be included, studies had to include more than 10 patients and have a treatment duration of at least 2 weeks. Studies of GH therapy showed significant increases in lean body mass compared with placebo. Two studies evaluating GH treatment found statistically significant improvements in some aspects of quality of life after 12 weeks. A 2005 double-blind RCT by Evans et al. included 700 patients with HIV-associated wasting. (36) Patients assigned to human GH had significantly greater increase in exercise capacity (the primary outcomes) than patients assigned to placebo.
Section Summary: AIDS Wasting
A systematic review of the literature found significant improvement in lean body mass with GH therapy versus placebo; several found improvements in quality of life. A subsequent RCT with a large sample size found a significantly greater increase in exercise capacity with GH treatment than with placebo.
Short Bowel Syndrome (SBS) with Specialized Nutritional Support
SBS is experienced by patients who have had 50% or more of the small intestine removed. This procedure results in malnourishment because the remaining small intestine is unable to absorb enough water, vitamins, and other nutrients from food. The FDA label for Zorbtive® indicates that GH has been shown in human clinical trials to enhance the transmucosal transport of water, electrolytes, and nutrients. According to the product label, FDA approval for Zorbtive® was based on the results of a randomized, controlled, phase 3 trial in which patients dependent on intravenous parenteral nutrition who received Zorbtive® (either with or without glutamine) over a 4-week period had significantly greater reductions in the weekly total volume of intravenous parenteral nutrition required for nutritional support. However, the effects beyond 4 weeks were not evaluated nor were treatment locations (inpatient versus outpatient) identified.
A 2010 Cochrane review identified 5 RCTs evaluating GH therapy for treating SBS. (37) Studies evaluated GH with or without glutamine treatment. The primary outcome was change in body weight. A pooled analysis of 3 small trials (n=30 patients) found a statistically significant difference in weight change when patients were treated with GH or placebo (MD=1.66 kg; 95% CI, 0.69 to 2.63 kg; p<0.001).
Several published studies have also demonstrated improved intestinal absorption in short bowel syndrome patients receiving parenteral nutrition. (38, 39) However, studies have noted that the effects of increased intestinal absorption are limited to the treatment period. (39, 40) Specialized clinics may offer intestinal rehabilitation for patients with short bowel syndrome; GH may be 1 component of this therapy.
Section Summary: Short Bowel Syndrome with Specialized Nutritional Support
A pooled analysis of 3 small RCTs found a significantly greater weight gain with GH therapy compared with placebo, and others studies have found improved intestinal absorption on patients with short bowel syndrome receiving parenteral nutrition.
Small for Gestational Age (SGA) Children
A meta-analysis of RCTs evaluating GH treatment for children born SGA was published in 2009. (41) Four trials (total N=391 children) met the eligibility criteria (birth height or weight <2 SDS, initial height <2 SDS). The GH dose ranged from 33 to 67 μg/kg in the RCTs, and mean duration of treatment was 7.3 years. Mean adult height in the 4 studies was -1.5 SDS in the treated group and -2.4 SDS in the untreated group. Adult height in the treated group was significantly higher than that of controls (MD=0.9 SDS [5.7 cm]; p<0001). There was no difference in adult height between the 2 doses of 33 and 67 μg/kg/d. The reviewers noted that it is unclear whether the gain in adult height associated with GH treatment “is of sufficient clinical importance and value to warrant wide-spread treatment of short children born SGA [small for gestational age].…”
There are very few data on the psychosocial outcomes of short pediatric or adult stature related to intrauterine growth retardation and how these outcomes may be affected by GH therapy. As noted, data are inadequate to document that short-stature youths have either low self-esteem or a higher than average number of behavioral or emotional problems.
Section Summary: Small for Gestational Age Children
A meta-analysis found that GH treatment resulted in significantly greater adult height in SGA children than a control treatment. There are few data on psychological or functional outcomes associated with this additional gain in height.
Altered Body Habitus Related to Antiretroviral Therapy for HIV Infection
There is research on the use of GH for altered body habitus that may be a complication of antiretroviral therapy for HIV infection. Body habitus changes, also referred to as the fat redistribution syndrome, include thinning of the face, thinning of the extremities, truncal obesity, breast enlargement, or an increased dorsocervical fat pad ("buffalo hump"). (42) However, there is scant published literature on the use of GH for this indication. The literature is dominated by letters to editors and small case series. The largest case series was reported by Wanke et al. who treated 10 HIV-infected patients with fat redistribution syndrome with GH for 3 months. (43) The authors reported improved waist/hip ratio and mid-thigh circumference.
Section Summary: Altered Body Habitus Related to Antiretroviral Therapy for HIV Infection
A single RCT reporting change in visceral abdominal fat provides insufficient evidence that GH treatment improves health outcomes in HIV-infected patients with altered body habitus related to antiretroviral therapy. Additional studies reporting a wider range of outcomes are needed.
Children with Idiopathic Short Stature (ISS) (Without Documented GHD or Underlying Pathology)
Impact on Adult Height
Several meta-analyses have been published. Most recently, in 2011, Deodati and Cianfarani identified 3 RCTs and 7 non-RCTs. (44) Selection criteria for the systematic review, included prepubertal children with ISS (>2 SD below the mean) and peak GH response greater than 10 μg/L. In addition, participants could not have had previous GH therapy or comorbid conditions that could impair growth. Adult height was defined as a growth rate of less than 1.5 cm/y or bone age was 15 years in females and 16 years in adults. The primary efficacy outcome was the difference between groups in adult height; this was measured as an SDS. The investigators considered an MD in height of more than 0.9 SDS (»6 cm) to be a satisfactory response to GH therapy. Only 1 RCT was placebo-controlled, and that trial had a high dropout rate (40% in the treated group, 65% in the placebo group).
In the 3 RCTs (n=115), the mean adult height (primary efficacy outcome) was -1.52 SDS for treated children and -2.30 SDS for untreated children. The difference between groups significantly favored the treated group (MD=0.65 SDS [»4 cm]; 95% CI, 0.40 to 0.91; p<0.001). The mean adult height in the 7 nonrandomized studies was -1.7 SDS for treated children and -2.1 SDS for untreated children. The MD between groups was 0.45 SDS (3 cm) (95% CI, 0.18 to 0.73) and was statistically significant favoring the treated group (p<0.001). Although GH treatment resulted in a statistically significant increase in adult height in the treated group, according to the a priori definition of a satisfactory response, the difference was not clinically significant. Moreover, there was a lack of high-quality, placebo-controlled RCTs.
In 2007, a Cochrane review by Bryant et al. evaluated GH therapy for ISS in children and adolescents. (45) Ten RCTs met eligibility criteria, which included studies being conducted in children who had normal GH secretion, normal size for gestational age at birth, and no evidence of chronic organic disease. In addition, studies had to compare GH treatment with placebo or no treatment and provide GH treatment for at least 6 months. Three studies were placebo-controlled, and the other 7 compared GH therapy with no treatment. Unlike the Deodati and Cianfarani review (previously described), studies were not required to report final adult height. Nine of 10 studies in the Cochrane review were short term and reported intermediate outcomes. A pooled analysis of 3 studies reporting growth velocity at 1 year found a statistically significant greater growth velocity in treated than in untreated children. The weight mean difference (WMD) was 2.84 (95% CI, 2.06 to 2.90). Five studies reported height SDSs, but there was heterogeneity among studies and the findings were not pooled. These data suggest that GH has an effect on height in children with ISS in the short term but that evidence on GH’s effects on adult height is extremely limited.
Impact on Self-Esteem and Quality of Life
Advocates of GH therapy often cite the potential psychosocial impairments associated with short stature. Several RCTs have addressed this issue, and did not find better self-esteem, psychological functioning, or quality of life in children treated with GH compared with controls. These studies are briefly described next.
In 2004, Ross et al. published findings on psychological adaptation in 68 children with ISS without GHD. (46) Children (mean age, 12.4 years) were randomized to receive GH therapy (n=37) or placebo (n=31) 3 times per week until height velocity decreased to less than 1.5 cm/y. At baseline and then yearly, parents and children completed several psychological instruments including the Child Behavior Checklist (CBCL) and Self-Perception Profile (SPP). No significant associations were found between attained height SDS or change in height SDS and annual changes in scores on the CBCL. There were no significant differences between groups on any CBCL summary scales in years 1 and 2, but, in year 4, there were significantly higher scores on the CBCL summary scales in the group receiving GH treatment. There were no significant differences between groups on the SPP at any follow-up point. This study did not find a correlation between short stature and psychological adaptation or self-concept.
Theunissen et al. in the Netherlands published a trial in 2002 in which 40 prepubertal children with ISS were randomly assigned to GH treatment (n=20) or a control group (n=20). (47) Parents and children were interviewed at baseline and at 1 and 2 years to obtain information on health-related quality of life (HRQOL) and children’s self-esteem. At the 2-year follow-up, satisfaction with current height was significantly associated with improvement in children’s reported HRQOL, social functioning, and other psychosocial measures. However, satisfaction with height did not differ significantly between the treatment and control groups. The data from this study do not support the hypothesis that GH treatment improves HRQOL in children with ISS.
In 1996, Downie et al. examined the behavior of children without documented GHD who were treated with GH due to idiopathic short stature. (48) Across measures of behavior, including IQ, self-esteem, self-perception, or parental perceptions of competence, there were no significant differences between the control and the treatment groups, either at baseline or after 5 years of GH therapy. The authors concluded that while no psychosocial benefits of GH therapy have been demonstrated, likewise, no documented psychosocial ill effects of GH treatment have been demonstrated.
Section Summary: Children with Idiopathic Short Stature
Systematic reviews have found that GH treatment may increase height gain for children with idiopathic short stature, but the difference in height gain may not be clinically significant. The absolute difference in height in these studies ranged from 3 to 4 cm, and children treated with GH remained below average in height, with heights between 1 and 2 SD below the mean at the end of treatment. These studies did not follow treated patients long enough to determine the ultimate impact of GH on final adult height.
RCTs have not found that short stature is associated with psychological problems, contrary to the expectations of some advocates. In addition, the available trials have not reported a correlation between increases in height and improvements in psychological functioning. Moreover, this group of children is otherwise healthy and there are potential risks to GH therapy in childhood (see previous section Safety of Growth Hormone Treatment).
Children with “Genetic Potential”
No randomized or nonrandomized studies were identified that have evaluated the efficacy, safety, and/or psychosocial impacts of treating children with “genetic potential” (i.e., children with lower than expected high percentiles based on their parents’ height).
Treatment of Precocious Puberty in Conjunction with GnRH Therapy
Precocious puberty is generally defined as the onset of secondary sexual characteristics before 8 years of age in girls and 9 years in boys. Central precocious puberty is related to hypothalamic pituitary gonadal activation, leading to increase in sex steroid secretion, which accelerates growth and causes premature fusion of epiphyseal growth plates, thus impacting final height. Children with precocious puberty are often treated with GnRH analogues to suppress the pituitary gonadal activity, to slow the advancement of bone age, and to improve adult height.
One RCT compared GnRH analogues alone versus GnRH analogues combined with GH therapy. This trial, by Tuvemo et al., included 46 girls with precocious puberty. (49) Criteria for participation did not include predicted adult height or growth velocity. After 2 years of treatment, mean growth and predicted adult height were greater in those receiving combined treatment than in those receiving GnRH analogues alone. The absence of final height data limits interpretation of this trial.
In addition, a case series from Italy reported on 17 girls with precocious puberty and a growth velocity below the 25th percentile who were treated with a combination of GnRH and GH, and 18 girls who refused treatment with adjunctive GH. (50) Those in the combined group attained a significantly greater adult height (161.2 cm) than the “control” group (156.7 cm). This small study is inadequate to permit scientific conclusions.
Section Summary: Treatment of Precocious Puberty in Conjunction with GnRH Therapy
There are insufficient data on the incremental benefit of GH added to GnRH therapy in patients with precocious puberty. One RCT was published, but final height was not reported. One small comparative case series found significantly higher adult height with adjunctive GH therapy, but this study may have been subject to confounding. No studies have reported functional or psychological outcomes.
Older Adults with Age-Related Growth Hormone Deficiency (GHD)
A 2001 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment investigated the use of GH in older adults with age-related growth hormone deficiency and concluded that there was insufficient evidence of efficacy. (51) It is not possible to prove effectiveness of GH treatment or lack thereof unless otherwise similar groups of treated versus nontreated patients are compared over a sufficient length of time to allow detection of any significantly and clinically different results.
Section Summary: Older Adults with Age-Related GHD
The BCBSA TEC Assessment concluded that there is a lack of evidence that GH therapy in older adults improves health outcomes. No subsequent controlled studies were identified.
Cystic Fibrosis (CF)
A 2013 Cochrane systematic review evaluated GH therapy for improving lung function, nutritional status, and quality of life in children and young adults with cystic fibrosis. (52) The reviewers identified 4 RCTs (total N=161 participants). All studies used daily subcutaneous injection of rhGH as the intervention and included a no treatment or placebo control group. All studies measured pulmonary function and nutritional status. However, due to differences in how these outcomes were measured, study findings were not pooled.
Previously, a 2010 systematic review identified 10 controlled trials evaluating GH for treating patients with CF. (53) One study was placebo-controlled, 8 compared GH therapy with no treatment, and the remaining trial compared GH alone with glutamine or glutamine plus GH. In 1 study, patients were treated with GH for 4 weeks and, in the others, durations of treatment ranged from 6 months to 1 year. There were insufficient data to determine the effect of GH on most health outcomes including frequency of intravenous antibiotic treatment, quality of life, and bone fracture. Data were pooled for 1 outcome, frequency of hospitalizations. In trials lasting at least 1 year, there were significantly lower rates of hospitalizations per year in groups receiving GH therapy (pooled effect size, -1.62; 95% CI, -1.98 to -1.26).
One of the RCTs was an industry-sponsored, open-label study published by Stalvey et al. in 2012. (54) It compared GH therapy with no treatment in prepubertal children with cystic fibrosis who were younger than 14 years old. Eligibility criteria included height no more than the 10th percentile for age and sex; children with documented GHD were excluded. Participants were treated daily for 12 months and followed for another 6 months. The study included 68 children; 62 (91%) were included in the efficacy analysis, and all but 1 were included in the safety analysis. Annualized height velocity at month 12 was 8.2 cm/y (SD=2.1) in the treatment group and 5.3 cm/y (SD=1.3) in the control group; the difference between groups was statistically significant (p<0.001). Mean height SDS in the treatment group was -1.8 at baseline, -1.4 at 12 months, and -1.4 at 18 months. Mean height SDS in the control group was -1.9 at all 3 time points. Change in mean height SDS from baseline to 12 months was significantly greater in the treatment than in the control group (p<0.001). Between months 12 and 18 (after treatment ended), the control group remained at the same height SDS, while the treatment group experienced a slight decline (0.1 SDS), but maintained a 0.5 SDS advantage over the control group.
In terms of pulmonary outcomes, the unadjusted rate of change from baseline to 12 months in most variables (7/8 pulmonary test results) did not differ between groups. However, the unadjusted change from 12 to 18 months (after treatment ended) was significantly greater in the control group than in the treatment group for 4 of 7 pulmonary test variables, including forced expiratory volume in 1 second (FEV1) (p<0.005) and forced vital capacity (p<0.01). In the treatment group, mean FEV1 was 1209 liters (SD=451) at baseline, 1434 liters (SD=539) at 12 months, and 1467 liters (SD=568) at 18 months compared with 1400 liters (SD=495) at baseline, 1542 liters (SD=510) at 12 months, and 1674 liters (SD=510) at 18 months in the control group. From baseline to 12 months, the between-group difference in change in the 6-minute walk distance was 26.3 meters (95% CI, -44.8 to 97.4 meters; p=0.46). Ten children in the treatment group and 9 in the control group were hospitalized for pulmonary exacerbations during the 12-month study period; the difference between groups was not statistically significant. In general, treatment with GH resulted in statistically significant improvements in height SDS but did not significantly improve outcomes associated with CF.
Section Summary: Cystic Fibrosis
Several RCTs and systematic reviews have been published. The RCTs were heterogenous and reported a variety of outcomes. One systematic review did not pool results for most outcomes, including frequency of intravenous antibiotic treatment, quality of life, and bone fracture. The pooled data on 1 outcome (hospitalizations) found significantly fewer hospitalizations in patients receiving GH therapy versus no treatment or placebo.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 1.
Table 1. Summary of Key Trials
A Randomized Controlled Trial of the Use of Aromatase Inhibitors, Alone and in Combination with Growth Hormone in Adolescent Boys with Idiopathic Short Stature
The Influence of Growth Hormone (GH) Therapy on Short Stature Related Distress a Prospective Randomized Controlled Trial
NCT: National Clinical Trial;
a: Denotes industry-sponsored or cosponsored trial.
Practice Guidelines and Position Statements
Pediatric Endocrine Society (PES)
In 2015, the PES published an evidence-based report on risk of neoplasia in patients receiving GH therapy. (55) The report concluded that GH therapy can be administered without concerns about impact on neoplasia in children without known risk factors for malignancy. For children with medical conditions associated with an increased risk of future malignancies, patients should be evaluated on an individual basis and decisions made about the tradeoff between a possible benefit of GH therapy and possible risks of neoplasm.
Growth Hormone Research Society (GHRS)
In 2013, a GHRS workshop issued consensus guidelines on rhGH therapy in Prader-Willi syndrome. (56) The following were among the group’s recommendations:
• “After genetic confirmation of the diagnosis of PWS [Prader-Willi Syndrome], rhGH treatment should be considered and, if initiated, should be continued for as long as demonstrated benefits outweigh the risks.”
• “GH stimulation testing should not be required as part of the therapeutic decision-making process in infants and children with PWS.”
• “Exclusion criteria for starting rhGH in patients with PWS include severe obesity, uncontrolled diabetes, untreated severe obstructive sleep apnea, active cancer, and active psychosis.”
• “Scoliosis and cognitive impairment should not be considered exclusion criteria.”
Endocrine Society (ES)
An ES clinical practice guideline on adult GHD, updated in 2011, includes the following statements (57):
• The Task Force recommends that GH therapy of GH-deficient adults offers significant clinical benefits in body composition and exercise capacity.
• The Task Force suggests that GH therapy of GH-deficient adults offers significant clinical benefits in skeletal integrity.
• The Task Force recommends after documentation of persistent GHD that GH therapy be continued after completion of adult height to obtain full skeletal/muscle maturation during the transition period.
National Institute of Health and Clinical Excellence (NICE)
In 2010, the NICE issued guidance on rhGH for growth failure in children. (58) NICE recommended GH as a possible treatment for children with growth failure who have any of the following conditions:
• Growth hormone deficiency,
• Turner syndrome,
• Prader-Willi syndrome,
• Chronic renal insufficiency,
• Small for gestational age and have growth failure at 4 years,
• Short stature homeobox (SHOX) gene deficiency.
American Association of Clinical Endocrinologists (AACE)
In 2009, the AACEs issued updated guidelines on GH use in GH-deficient adults and transition patients. (59) Evidence-based recommendations included the following:
• Growth hormone deficiency (GHD) is a well-recognized clinical syndrome in adults that is associated with significant comorbidities if untreated.
• Growth hormone (GH) should only be prescribed to patients with clinical features suggestive of adult growth hormone deficiency and biochemically proven evidence of adult growth hormone deficiency.
• No data are available to suggest that GH has beneficial effects in treating aging and age-related conditions and the enhancement of sporting performance; therefore, the guideline developers do not recommend the prescription of GH to patients for any reason other than the well-defined approved uses of the drug.
Growth Hormone Research Society (GHRS) et al.
In 2008, the GHRS, Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop published a consensus statement on the diagnosis and treatment of children with ISS. (60) The statement indicated that the appropriate height below which GH treatment should be considered ranged from -2 to -3 SDS. The optimal age for treatment was thought to be between 5 years and early puberty. The group noted that psychological issues should be considered (e.g., GH therapy should not be recommended for short children who are unconcerned about stature).
In early 2016, results from the Growth Hormone Safety Workshop were published in the European Journal of Endocrinology. (61) The workshop was convened by GHRS and other medical societies. The purpose of the workshop was to reappraise the safety of rhGH. The position statement concluded:
• After following children and adults for tens of thousands of person-years, the safety profile of rGH remains good when rhGH is used for approved indications and at recommended doses. There is no evidence supporting an association between rhGH and overall mortality, risk of new primary cancer, risk of recurrence of primary cancer, risk of stroke, or risk of cardiovascular disease.
• A carefully designed cohort study, providing continued long-term surveillance of patients treated with rhGH, would address the current limitations of safety data (e.g., inconsistent definitions of outcomes, low incidence outcomes, and lack of dose-specific assessments).
American Academy of Pediatrics (AAP)
In 1997, the AAP published a document that recommended the following patient selection criterion for children with short stature not associated with classic GH deficiency (62):
“Therapy with GH is medically and ethically acceptable in patients whose extreme short stature keeps them from participating in basic activities of daily living and who have a condition for which the efficacy of GH therapy has been demonstrated.”
Summary of Evidence
For individuals who have proven growth hormone deficiency (GHD) who receive human growth hormone (GH), the evidence includes randomized controlled trials (RCTs), large observational studies, and meta-analyses. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. Studies have found that, for patients with documented GHD and clinical manifestations such as short stature, GH replacement has been shown to improve growth velocity and final height achieved. In addition, studies have shown that GH therapy can ameliorate the secondary manifestations of GHD such as increase in lean muscle mass and bone mineral density seen primarily in older children and adults. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have short stature due to Prader-Willi syndrome who receive human GH, the evidence includes RCTs. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. Several RCTs have found improvement in height and other outcomes (e.g., motor development) in children with Prader-Willi syndrome. Studies have found increased risk of adverse events in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment and thus GH is contraindicated. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have short stature due to chronic renal insufficiency who receive human GH, the evidence includes RCTs and systematic reviews. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. Systematic reviews of RCTs have found significantly increased height and height velocity in children with short stature associated with chronic renal insufficiency who are treated with GH therapy compared with other interventions. There were no significant increases in adverse events related to renal function. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have short stature due to Turner syndrome who receive human GH, the evidence includes RCTs. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. RCTs have found that GH therapy increases height outcomes (e.g., final height, height velocity) in children with short stature due to Turner syndrome compared with placebo or no treatment. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have short stature due to Noonan syndrome who receive human GH, the evidence includes observational studies and a systematic review. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. There are a number of studies; however, few included treatment comparators. A systematic review found that GH therapy was associated with an increase in height in patients with Noonan syndrome. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have short stature due to short stature homeobox-containing gene (SHOX) deficiency who receive human GH, the evidence includes an RCT and systematic review. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. An RCT found that children with short stature due to SHOX deficiency had significantly greater height velocity and height gain after 2 years when treated with GH versus no GH treatment. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have severe burns who receive human GH, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, hospitalizations, and treatment-related morbidity. Numerous RCTs evaluating GH for treatment of severe burns have been published. Pooled analyses have found significantly shorter healing times and significantly shorter hospital stays with GH therapy than with placebo. Several RCTs have found significantly greater height gain in children with burns who received GH therapy versus placebo or no treatment. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have AIDS wasting who receive human GH, the evidence includes observational studies, at least 1 RCT, and a systematic review. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. A systematic review found significant improvement in lean body mass with GH therapy versus placebo; several studies found improvements in quality of life. A subsequent RCT with a large sample size found a significantly greater increase in exercise capacity with GH than with placebo. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have short bowel syndrome on specialized nutritional support who receive human GH, the evidence includes RCTs and a meta-analysis. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. A pooled analysis of 3 small trials found significantly greater weight gain with GH therapy than with placebo and others studies found improved intestinal absorption on patients with short bowel syndrome receiving parenteral nutrition. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who are small for gestational age (SGA) who receive human GH, the evidence includes RCTs and a meta-analysis. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. A meta-analysis found that GH treatment resulted in significantly greater adult height in SGA children than a control treatment. There are few data on the psychological or functional outcomes associated with this additional gain in height. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have altered body habitus related to antiretroviral therapy for HIV infection who receive human GH, the evidence includes case series. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. Case series data are insufficient for drawing conclusions about the impact of GH treatment on health outcomes in HIV-infected patients with altered body habitus related to antiretroviral therapy. Controlled studies reporting relevant outcomes are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have idiopathic short stature (ISS) who receive human GH, the evidence includes RCTs and systematic reviews. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. Systematic reviews have found that GH treatment may increase height gain for children with ISS, but the difference in height gain may not be clinically significant. The available studies did not follow treated patients long enough to determine the ultimate impact of GH on final adult height. RCTs have not found that short stature is associated with psychological problems, contrary to the expectations of some advocates. In addition, the available trials have not reported a correlation between increases in height and improvements in psychological functioning. Moreover, this group of children is otherwise healthy and there are potential risks to GH therapy in childhood. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have “genetic potential” (i.e., lower than expected height percentiles based on parents’ height) who receive human GH, the evidence includes no clinical trials. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. No published literature was identified on GH therapy as a treatment of children with “genetic potential.” The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have precocious puberty who receive human GH plus gonadotropin-releasing hormone (GnRH), the evidence includes an RCT and comparative case series. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. There are insufficient data on the incremental benefit of GH plus GnRH therapy in patients with precocious puberty. One RCT was published, but final height was not reported. One small comparative case series found significantly higher adult height with adjunctive GH therapy, but this study may have been subject to confounding. No studies reported functional or psychological outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who are older adults with age-related growth hormone deficiency who receive human GH, the evidence includes a systematic review (BCBSA TEC Assessment). Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. The BCBSA TEC Assessment concluded there is a lack of evidence that GH therapy in older adults improves health outcomes. No subsequent controlled studies were identified. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have cystic fibrosis (CF) who receive human GH, the evidence includes RCTs and a systematic review. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. Several RCTs and systematic reviews have been published. The RCTs were heterogenous and reported various outcomes. One systematic review did not pool outcomes on most outcomes, including frequency of intravenous antibiotic treatment, quality of life, and bone fracture; but the single pooled analysis found fewer hospitalizations in patients receiving GH therapy versus no treatment or placebo. The evidence is insufficient to determine the effects of the technology on health outcomes.
Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.
Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.
The following codes may be applicable to this Medical policy and may not be all inclusive.
J2940, J2941, S9558
ICD-9 Diagnosis Codes
Refer to the ICD-9-CM manual
ICD-9 Procedure Codes
Refer to the ICD-9-CM manual
ICD-10 Diagnosis Codes
Refer to the ICD-10-CM manual
ICD-10 Procedure Codes
Refer to the ICD-10-CM manual
The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.
A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
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|4/15/2017||Document updated with literature review. Coverage unchanged.|
|2/15/2016||Reviewed. No changes.|
|7/15/2015||Document updated with literature review. The following coverage criteria were added to Growth hormone deficiency in children noted in the documentation of proven GHD section: central nervous system pathology; genetic defect (Refer to Turner’s syndrome, Prader-Willi syndrome, or Noonan’s syndrome). The following coverage criteria was added to Short-stature in children; proven SHOX (Short-stature homeobox-containing gene) deficiency. Rationale and References reorganized.|
|9/15/2012||Document updated with literature review. Coverage remains conditional based on meeting growth hormone deficiency criteria; clarified use in growth failure when used for Prader-Willi syndrome, inflammatory bowel disease, and advanced aging; and coverage added for Noonan’s syndrome. Treatment of children with “genetic potential” (i.e., lower than expected height percentile based on parents’ height) included as experimental, investigational and unproven. Clarified and expanded explanation of each FDA approved rhGH drug and their indication(s). CPT/HCPCS code(s) updated.|
|8/1/2007||Document updated with literature review.|
|3/23/2005||Document updated with coverage change.|
|6/1/2004||Document updated with coverage change.|
|12/1/2003||Document updated with literature review.|
|2/1/2002||CPT/HCPCS code(s) updated ( with bit changes ).|
|6/1/2001||CPT/HCPCS code(s) updated ( with bit changes ).|
|1/1/2000||Document updated with literature review.|
|2/1/1998||Document updated with literature review.|
|5/1/1996||Document number changed.|
|4/1/1993||Document updated with literature review.|
|9/1/1990||New medical document.|
|Title:||Effective Date:||End Date:|
|Growth Hormone (GH)||04-15-2017||07-14-2018|
|Growth Hormone (GH)||02-15-2016||04-14-2017|
|Growth Hormone (GH)||07-15-2015||02-14-2016|
|Growth Hormone (GH)||09-15-2012||07-14-2015|
|Growth Hormone (GH)||08-01-2007||09-14-2012|
|Growth Hormone (GH)||03-23-2005||07-31-2007|
|Growth Hormone (GH)||12-01-2003||03-22-2005|