Medical Policies - Prescription Drugs
Human 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, 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 specific indications and criteria (see Table 1 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]).
Table 1. MEDICALLY NECESSARY
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
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 2.0 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 1- to 2-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 10 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, who do not have the following contraindications:
• History of upper airway obstruction; or
• History of sleep apnea; or
• History of severe respiratory impairment.
NOTE 11: Sleep studies are recommended prior to initiation of GH therapy for obese pediatric patients with Prader-Willi syndrome. If there are signs that upper airway obstruction and sleep apnea could occur, GH should not be administered. If during treatment, patients develop signs of upper airway obstruction or new sleep apnea, treatment should be interrupted.
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.
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 Tables 2 and 3 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.
Table 2. NOT MEDICALLY NECESSARY
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 12 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. (83) 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. (76) The FDA-approved indication is for children with a height SD of -2.25 below the mean. (9) 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.
Table 3. EXPERIMENTAL, INVESTIGATIONAL and/or UNPROVEN
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).
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. Growth hormone deficiency (GHD) can occur due to a variety of conditions, such as:
• Pituitary tumor,
• Pituitary dysfunction due to prior surgery or radiation treatment,
• Extra pituitary 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.
For some conditions, the patient’s disorder/syndrome presents itself as a complex multisystem disorder characterized, such as Prader-Willi syndrome, a genetic disorder characterized by a microdeletion in the long arm of chromosome 15, by excessive appetite, obesity, short stature, characteristic appearance, developmental disability, and significant behavioral dysfunction. GHD has been demonstrated in most tested patients with Prader-Willi syndrome. Additionally, sleep studies are recommended prior to initiation of GH therapy for obese pediatric patients with Prader-Willi syndrome. If there are signs that upper airway obstruction and sleep apnea could occur, GH should not be administered. If during treatment, patients develop signs of upper airway obstruction or new sleep apnea, treatment should be interrupted.
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® and 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 GHD, 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.
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 GH. Currently, the FDA-labeled indications for Norditropin®/Nordiflex® include treatment of children with growth failure due to 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.
Recommended FDA labeled dosing: (9)
Dosing titration and management is individualized and based upon the patient’s age, weight, condition, disease state, and treatment response. Refer to the full prescribing information in the FDA-approved label for each GH.
There are phase 2 and phase 3 trials including children and adults that are currently ongoing, evaluating new GH formulations that are administered weekly rather than daily. (1-3) The new long-acting formulations have not received FDA approval at this time.
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 2018. The following discussion focuses on the most controversial aspects of growth hormone (GH) use.
Assessment of efficacy for therapeutic intervention involves a determination of whether an intervention improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes but are prone to biases such as noncomparability of treatment groups, placebo effect, and variable natural history of the condition.
Safety of GH Treatment
Adverse events 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 adverse events include pancreatitis and gynecomastia. (4, 5) 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. (6) 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 vs 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. (7) 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 beenSGA 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.
In 2017, Swerdlow et al. published results from the Safety and Appropriateness of Growth Hormone Treatments in Europe study, which compared the risk of cancer mortality and cancer incidence among patients receiving GH therapy with national population rates. (8) For the cancer mortality analysis, the cohort consisted of 23,984 patients from 8 European countries. For the cancer incidence analysis, only those patients from countries with highly complete cancer registries (Belgium, Netherlands, Sweden, Switzerland, United Kingdom) were included (n=10,406). Over 50% received GH treatment due to “isolated growth failure,” defined as GHD, idiopathic short stature, and prenatal growth failure. Other common diagnoses leading to GH treatment included: Turner syndrome, pituitary hormone deficiency, and central nervous system tumor. For the cancer mortality cohort, mean follow-up was 17 years, mean age at follow-up was 27 years, and there were 251 cancer deaths. For the cancer incidence cohort, mean follow-up was 15 years, mean age at last follow-up was 26 years, and there were 137 incident cancers. For patients whose initial diagnosis was “isolated growth failure,” overall cancer risk was not elevated. For patients whose initial diagnosis was not cancer, neither cancer mortality nor cancer incidence was related to age of treatment initiation and duration of treatment.
According to drug prescribing information, GH therapy use has been associated with sudden death in children with Prader-Willi syndrome. (9, 10) These deaths occurred among children who were severely obese or had severe respiratory impairment; these markers are now considered contraindications to GH treatment in patients with Prader-Willi syndrome.
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. (11) 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 2006 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. (12)
GHD in Adults
In adults with GHD, evidence from RCTs has shown that treatment leads to increases in lean body mass and decreases in body fat. (13) Meta-analyses of RCTs have shown evidence for increases in muscle strength and exercise capacity, although these findings were not robust across all studies. (14, 15) There is also evidence from meta-analyses that GH therapy is associated with increased bone mineral density (BMD) in adults with GHD. (16, 17) For example, a 2014 meta-analysis by Barake et al. identified 9 placebo-controlled randomized trials with at least 1-year follow-up on the effect of daily GH therapy on BMD. (17) 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 (e.g., quality of life, lipid profiles, cardiovascular disease, total mortality) was inconsistent and insufficient to determine whether these outcomes improved with treatment. (18-21)
Section Summary: GHD
Large cohort studies, RCTs, and meta-analyses have found that, for children 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 and may increase lean muscle mass and BMD seen primarily in older children and adults.
Short Stature due to Prader-Willi Syndrome
Prader-Willi syndrome is a rare neurodevelopmental disorder characterized by muscular hypotonia, hypogonadism, short stature, obesity, psychomotor delay, neurobehavioral abnormalities, and cognitive impairment. 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).
There have been numerous case reports of sudden unexpected death in Prader-Willi syndrome patients undergoing GH therapy. (22-24) Causes of death included respiratory insufficiency and sleep apnea, suggesting that GH therapy may exacerbate respiratory impairment in patients with Prader-Willi syndrome. The product labels for GH treatments, therefore, warn that children with Prader-Willi syndrome be evaluated for signs of upper airway obstruction and sleep apnea prior to initiation of treatment and that treatment should be discontinued if these signs occur. (9, 10)
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). (25) 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. (26) 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. (27) 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, followed by a cohort study of the children on GH therapy for an additional 6 years. (28) 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.
In 2016, Kuppens et al. published results from a 2-year crossover, blinded, placebo-controlled randomized trial designed to investigate the effects of GH on body composition in young adults with Prader-Willi syndrome who were treated with GH during childhood and had attained adult height. (29) Patients (N=27) were stratified by sex and body mass index and randomized to GH injections once daily or placebo injections. After 1 year, the patients received the alternate treatment. Every 3 months, fat mass and lean body mass were measured by dual-energy x-ray absorptiometry. GH treatment resulted in lower mean fat mass (-17.3%) and higher lean body mass (+3.5%) compared with placebo.
Section Summary: Short Stature due to Prader-Willi Syndrome
Several RCTs have found improvements in height, body mass index, head circumference, and motor development in children with Prader-Willi syndrome treated with GH. GH treatment was not found to significantly change problem behavior or total IQ. In a blinded crossover RCT, patients with Prader-Willi syndrome, who were treated with GH as children and had attained adult height experienced lower fat mass and higher lean body mass when treated with GH compared with placebo. 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 systematic review of RCTs evaluating the impact of GH therapy on height outcomes following renal transplant in children ages 0 to 18 years. (30) 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. (31) 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 pre-dialysis, 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. (1991), conducted in the Netherlands. (32) 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. (33) 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.
Primary outcomes in most studies of GH for the treatment of children with chronic kidney disease are height or height velocity. A 2017 case control study by Bizzarri et al. compared the final height of children treated (n=68) and not treated (n=92) with GH who had chronic kidney disease. (34) Mean follow-up was 9 years. Among cases, the mean duration of GH therapy was 4 years. Height SDS significantly improved from baseline to final height in GH-treated children, while there was a slight but nonsignificant decrease in height SDS among non-GH-treated children. However, final height SDS did not differ significantly between treated and nontreated children (p=0.3). The reason for no difference in final height might have been that the nontreated children had a significantly higher height SDS at baseline compared with the treatment group. This difference may be why GH treatment was not initiated in the control group.
Section Summary: Short Stature due to Chronic Renal Insufficiency
Numerous RCTs and systematic reviews of 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 a characteristic of 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. In one study, 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 cm (57.5 in) compared with an untreated control group who achieved a final height of 142.1 cm (56 in). (10)
In 2007, a Cochrane review identified 4 RCTs (total n=365 patients) evaluating GH for treating Turner syndrome. (35) 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 reported that short-term growth velocity was greater in treated than in untreated children (MD=3 cm/y; 95% CI, 2 to 4 cm/y).
In addition to short stature, individuals with Turner syndrome also exhibit craniofacial characteristics such as shorter and flattened cranial bases and inclined maxilla and mandible. A 2016 cross-sectional study by Juloski et al. compared the craniofacial morphology of 13 patients who had Turner syndrome treated using GH with 13 patients who had Turner syndrome not treated using GH. (36) Mean age of participants was 17 years. Individuals in the treatment group had received GH for a mean of 5.8 years. Comparisons of lateral cephalometric radiographs showed that GH therapy significantly increased linear measurements, mainly influencing posterior and anterior face height, mandibular height and length, and maxillary length. Angular measurements and facial height ratio did not differ significantly between the treated and untreated groups.
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. GH therapy has also been found to have a positive effect on craniofacial development.
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. (37) 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 had to follow patients for at least 3 years. Twenty-three studies were identified in a literature search conducted through April 2014, and 6 studies (total n=177 patients) 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 single controlled study (MacFarlane et al., 2001 ), 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). Mean height gain in SDS ranged from 0.6 to 1.4 cm by national standards, and between 0.6 and 2.0 cm by Noonan standards. The data were limited by the paucity of controlled studies and lack of RCTs.
Section Summary: Short Stature due to Noonan Syndrome
Evidence consists of a systematic review including a controlled trial and 5 uncontrolled studies. The data is limited due to lack of comparative studies; however, the systematic review found that GH therapy is associated with an increase in height in patients with short stature due to Noonan syndrome.
Short Stature due to Short Stature Homeobox-Containing Gene (SHOX) Deficiency
A 2010 Health Technology Assessment on GH treatment of growth disorders in children identified an RCT evaluating GH therapy for children with short stature due to SHOX deficiency. (39) This industry-sponsored, open-label multicenter trial was published by Blum et al. in 2007. (40) 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 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 trial. 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 (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. At the end of the randomized phase, all patients were offered GH.
In 2017, Benabbad et al. published long-term height results and safety data from patients in the Blum RCT (described above) and from a subset of patients with short stature due to SHOX deficiency from the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). (41) GeNeSIS was a prospective, multinational, open-label, pediatric surveillance program examining long-term safety and efficacy of GH. The subset of the GeNeSIS population with SHOX deficiency consisted of 521 patients. Forty-nine of the 52 patients in the RCT enrolled in the long-term study. Patients in both studies will be followed until they achieve near-adult (final) height. Final height was defined as attaining one of the following criteria: height velocity less than 2 cm/y, hand x-ray showing closed epiphyses, or bone age older than 14 years for boys or older than 16 years for girls. At the time of the analysis, 90 patients from GeNeSIS and 28 patients from the RCT reached near-adult height. For the GeNeSIS patients, mean age at GH treatment initiation was 11.0 years, mean age at near-adult height was 15.7 years, and GH treatment duration was 4.4 years. For the RCT patients, mean age at GH initiation was 9.2 years, mean age at near-adult height was 15.5 years, and GH duration was 6.0 years. The most common treatment-emergent adverse events reported in the GeNeSIS patients were: precocious puberty (2.6%) and arthralgia (2.4%). The most common treatment-emergent adverse events reported in the RCT patients were: headache (18.4%) and congenital bowing of long bones (18.4%).
Section Summary: Short Stature due to SHOX 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. A long-term observational study reported that patients with SHOX deficiency were able to reach near-adult height after 4 to 6 years of 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. (42) 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). 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 (1995) measuring mortality included 54 adult burn patients who survived the first 7 postburn days. (43) 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. (1998) 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%). (44) Another placebo-controlled trial (2002) found no benefit to GH with regard to length of hospitalization in 24 adults with severe burns. (45)
These results are consistent with a 1996 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment that evaluated the use of GH treatment for GH therapy for a variety of catabolic illnesses. (46) It found that, based on 6 trials, the use of GH treatment meets the BCBSATEC criteria to improve wound healing in patients with burns.
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. (47) 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. (48)
Section Summary: Severe Burns
Numerous RCTs evaluating GH for treatment of severe burns have been identified. Pooled analyses found significantly shorter healing times and significantly shorter hospital stays with GH therapy vs placebo. Several RCTs have found significantly greater height gains in children with burns who received GH therapy vs placebo or no treatment.
In 2004, Moyle et al. published a systematic review and meta-analysis of controlled and uncontrolled studies on selected treatments of HIV wasting. (49) To be included, studies had to include more than 10 patients and have a treatment duration of at least 2 weeks. Pooled analysis of 3 studies using GH therapy showed significant increases in lean body mass compared with placebo (MD=3.1; 95% CI, 2.7 to 3.6). Pooled analysis of 6 studies reporting pre-post lean body mass measurements also showed significant increases following GH treatment (MD=2.7; 95% CI, 1.4 to 3.7). Two studies evaluating GH treatment found statistically significant improvements in some measurements of quality of life after 12 weeks.
A 2005 double-blind RCT by Evans et al. included 700 patients with HIV-associated wasting. (50) Patients were randomized to daily GH, alternate days of GH, or placebo. Patients assigned to daily GH had significantly greater increases in maximum exercise capacity (the primary outcome) than patients assigned to placebo.
Section Summary: AIDS Wasting
A systematic review and meta-analysis of the literature found significant improvements 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 maximum 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 somatropin (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, the FDA’s 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. (9, 10)
A 2010 Cochrane review identified 5 RCTs evaluating GH therapy for treating SBS. (51) 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 compared with placebo (MD=1.7 kg; 95% CI, 0.7 to 2.6 kg; p<0.001). Lean body mass, nitrogen absorption, and energy absorption also significantly increased in patients receiving GH therapy compared with controls.
Several published studies have also demonstrated improved intestinal absorption in SBS patients receiving parenteral nutrition. (52, 53) However, the Cochrane review and the studies noted that the effects of increased intestinal absorption are limited to the treatment period. (51, 53, 54) Specialized clinics may offer intestinal rehabilitation for patients with short bowel syndrome; GH may be a component of this therapy.
Section Summary: SBS with Specialized Nutritional Support
A pooled analysis of 3 small RCTs found a significantly greater weight gain with GH therapy compared with placebo, and other studies have found improved intestinal absorption on patients with SBS receiving parenteral nutrition.
Small for Gestational Age (SGA) Children
A meta-analysis of RCTs evaluating GH treatment for children born SGA age was published in 2009. (55) 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 33 and 67 μg/kg/d doses. 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 youths with short stature have either low self-esteem or a higher than average number of behavioral or emotional problems.
Section Summary: SGA Children
A meta-analysis found that GH treatment resulted in significantly greater adult height in children born SGA 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
Research has evaluated the use of GH for altered body habitus, which may be a complication of antiretroviral therapy for HIV infection. Body habitus changes, also referred to as fat redistribution syndrome or HIV-associated lipodystrophy syndrome, include thinning of the face, thinning of the extremities, truncal obesity, breast enlargement, or an increased dorsocervical fat pad (“buffalo hump”). (56) 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. (1999) who treated 10 HIV-infected patients with fat redistribution syndrome with GH for 3 months. (57) The authors reported improved waist/hip ratio and mid-thigh circumference.
Because high-dose GH has been associated with adverse events relating to inflammation, Lindboe et al. (2016) conducted a randomized, double-blind, placebo-controlled trial to test the effect of low-dose GH for the treatment of HIV-infected patients on retroviral therapy. (58) Participants were randomized to GH 0.7 mg/d (n=24) or placebo (n=18) for 40 weeks. The primary outcome was change in inflammation measured by C-reactive protein and soluble urokinase plasminogen activator receptor (suPAR), both of which increase with inflammation. After 40 weeks, low-dose GH significantly lowered C-reactive protein. Low-dose GH lowered suPAR as well, but the difference was not statistically significant, even after controlling for age, weight, smoking status, and lipodystrophy.
Section Summary: Altered Body Habitus Related to Antiretroviral Therapy for HIV Infection
A case series has reported improvements in visceral abdominal fat. An RCT comparing low-dose GH with placebo showed that the treatment could reduce inflammation experienced by HIV-infected patients who had 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 assessed the impact of ISS and adult height. Most recently, in 2011, Deodati and Cianfarani identified 3 RCTs and 7 non-RCTs. (59) Selection criteria for the systematic review included prepubertal children with initial short stature (>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 of 15 years in females and 16 years in males. The primary efficacy outcome was the difference between groups in adult height, measured as 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 randomized trial 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 patients), 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 (difference, 0.9 SDS), 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. (60) 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 seven 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 weighted mean difference was 2.84 (95% CI, 2.06 to 2.90). Five studies reported height SDSs, but there was heterogeneity among studies, and findings were not pooled. These data suggest that GH has an effect on height in children with idiopathic short stature 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. (61) Children (mean age, 12.4 years) were randomized to 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 the Self-Perception Profile. 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 Self-Perception Profile 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 randomized to GH treatment (n=20) or a control group (n=20). (62) 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 trial did not support the hypothesis that GH treatment improves health-related quality of life in children with ISS.
In 1996, Downie et al. examined the behavior of children without documented GHD who were treated with GH due to ISS. (63) 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 ISS
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 absolute difference in height in these studies ranged from 3 to 4 cm; further, children treated with GH remained below average in height, with heights between 1 and 2 SD below the mean at the end of treatment (Note: 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 Gonadotropin-Releasing Hormone (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.
In 2016, Liu et al. published a meta-analysis comparing GnRH with the combination therapy of GH with GnRH for the treatment of females with idiopathic central precocious puberty. (64) The literature search, conducted through December 2014, identified 6 RCTs (n=162) and 6 clinical controlled trials (n=247) for inclusion. Risk of bias in the RCTs was assessed using the Cochrane Collaboration checklist. Five of the RCTs were determined to have moderate risk of bias and 1 trial had a high risk of bias. The clinical controlled trials were assessed using the Methodological Index for NOnRandomized Studies (MINORS), based on 12 items, with an ideal global score of 24. Scores on MINORS for the 6 controlled trials ranged from 17 to 20, as none of the trials reported blinded outcome evaluation or prospective calculation of study size. Primary outcomes included final height, difference between final height and targeted height, and height gain. Among the 12 included studies, age of participants ranged from 4.6 to 12.2 years and treatment period of the combination therapy ranged from 6 months to 3 years. One RCT and 4 clinical controlled trials provided data for the meta-analyses. Results showed that patients receiving the combination therapy for at least 1 year experienced significantly greater final height, difference in final height and targeted height, and height gain compared with those receiving GnRH alone (MD=2.8 cm [95% CI, 1.8 to 3.9 cm], 3.9 cm [95% CI, 3.1 to 4.7 cm], and 3.5 cm [95% CI, 1.0 to 6.0 cm], respectively). When treatment duration was less than 1 year, no significant differences in the height outcomes were found.
One RCT compared GnRH analogues alone with GnRH analogues plus GH therapy. This trial, by Tuvemo et al. (1999), included 46 girls with precocious puberty. (65) 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 (Pucarelli et al., 2003) 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. (66) 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
Evidence for the incremental benefit of GH added to GnRH therapy in patients with precocious puberty consists of a systematic review and meta-analysis, plus an RCT and case series not included in the systematic review). One RCT and 4 controlled trials of moderate quality provided data for the meta-analyses. Small, but statistically significant differences were reported in final height (2.8 cm), in the difference between final height and targeted height (3.9 cm), and in height gain (3.5 cm) for patients who received the combination therapy for at least one year compared with patients receiving GnRH alone. Interpretation of results from the RCT and small comparative case series not included in the systematic review is limited because of methodologic issues. No studies have reported on the impact of short stature on functional or psychological outcomes.
Older Adults with Age-Related Growth Hormone Deficiency (GHD)
A 2001 BCBSA TEC Assessment investigated the use of GH in older adults with age-related GHD and concluded that there was insufficient evidence of efficacy. (67) 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
A 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 CF. (68) 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. Due to differences in how outcomes were measured, study findings were not pooled. Across studies, GH was found to improve intermediate outcomes such as height and weight; however, improvements in lung function were inconsistent. No significant changes in quality of life or clinical status were detected.
One of the RCTs was an industry-sponsored, open-label study published by Stalvey et al. in 2012. (69) It compared GH therapy with no treatment in prepubertal children with CF younger than 14 years old. Eligibility criteria included height less 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 trial included 68 children; 62 (91%) were included in the efficacy analysis, and all but one was included in the safety analysis. The 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 (p<0.001). The mean height SDS in the treatment group was -1.8 at baseline, -1.4 at 12 months, and -1.4 at 18 months. The mean height SDS in the control group was -1.9 at all 3 time points. The 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, 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 of 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 did not differ significantly (26.3 meters; 95% CI, -44.8 to 97.4 meters). Ten children in the treatment group and nine in the control group were hospitalized for pulmonary exacerbations during the 12-month trial 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 clinical outcomes associated with CF.
Previously, a 2010 systematic review identified 10 controlled trials evaluating GH for treating patients with CF. (70) One study was placebo-controlled, eight compared GH therapy with no treatment, and the remaining trial compared GH alone with glutamine or glutamine plus GH. Durations of treatment ranged from 4 weeks to 1 year. There were insufficient data to determine the effect of GH on most health outcomes (e.g., frequency of intravenous antibiotic treatment, quality of life, bone fracture). Data were pooled for a single 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).
Section Summary: CF
Several RCTs and systematic reviews have been identified. The RCTs were heterogenous and reported a variety of outcomes. None of the systematic reviews pooled results for outcomes (e.g., frequency of intravenous antibiotic treatment, quality of life, bone fracture). The single pooled outcome (number of hospitalizations) was significantly lower in patients receiving GH therapy vs no treatment or placebo. Across the trials, GH was found to improve intermediate outcomes such as height and weight; however, clinically meaningful outcomes relating to lung function were not consistently improved with GH.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 5.
Table 5. Summary of Key Trials
Phase III Clinical Study of Recombinant Human Growth Hormone Injection (JINTOPIN AQ) for Short Children with Small for Gestational Age (SGA)
Dec 2017 (still recruiting)
Phase III Clinical Trial for Assessment of Efficacy and Safety of DA-3002 (Recombinant Human Growth Hormone) in Short Children Born Small for Gestational Age
An Observational Phase IV Study for Prospective Follow-Up to Adult Height of a Cohort of Subjects Born Small for Gestational Age and Treated with Growth Hormone
Long-term Phase IV Multicenter Study on the Safety and Efficacy of Omnitrope® (rhGH) in Short Children Born Small for Gestational Age (SGA)
An Open, Multi-Center, Prospective and Retrospective Observational Study to Evaluate the Long-term Safety and Effectiveness of Growth Hormone (Eutropin Inj./Eutropin plus Inj.) Treatment with GHD, TS, CRF, SGA, and ISS in Children
A Randomized, Open-label, Two-arm Parallel Group, No Treatment Group-Controlled, Multicenter Phase III Study to Evaluate the Safety and Efficacy of Saizen® 0.067 mg/kg/Day subcutaneous Injection in Children with Idiopathic Short Stature
Mar 2015 (completed)
A Randomized Controlled Trial of the Use of Aromatase Inhibitors, Alone and in Combination with Growth Hormone in Adolescent Boys with Idiopathic Short Stature
Oct 2017 (completed)
The Influence of Growth Hormone (GH) Therapy on Short Stature Related Distress a Prospective Randomized Controlled Trial
Dec 2017 (completed)
Special Investigation for Genotropin (SGA Long-term Follow-up)
Fe 2017 (completed)
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 focusing on the risk of neoplasia in patients receiving GH therapy. (71) 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.
As an addendum to the 2015 guidelines, Grimberg and Allen (2017), coauthors of the guidelines, published a historical review of the use of GH. (72) They asserted that although the guidelines did not find an association between GH and neoplasia, the use of GH should not necessarily be expanded. While the use of GH for patients with growth hormone deficiency (GHD) is recommended, evidence gaps persist in the use of GH for other indications such as idiopathic short stature and partial isolated GHD.
In 2016, the PES published guidelines for GH and insulin-like growth factor I-treatment for children and adolescents with GHD, idiopathic short stature, and primary insulin-like growth factor-I deficiency. (73) The guidelines used the GRADE approach (grading of recommendations, assessment, development, and evaluation). The following recommendations were made:
• “We recommend the use of GH to normalize adult height and avoid extreme shortness in children and adolescents with GHD. (strong recommendation, high quality evidence)
• “We suggest a shared decision-making approach to pursuing GH treatment for a child with idiopathic short stature. 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 [standard deviation score] ≤ -2.25. (conditional recommendation, moderate quality evidence)
In 2017, PES published clinical practice guidelines for the management of Turner syndrome based on proceedings of the International Turner Syndrome Meeting. (74) PES recommended initiating GH treatment early, around 4 to 6 years of age, and preferably before 12 to 13 years if the child has evidence of growth failure (<50th percentile height velocity) or has strong likelihood of short stature (moderate quality of evidence).
Endocrine Society (ES)
An ES clinical practice guideline on adult GHD, updated in 2011, includes the following statements (75):
• 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. (76) The Institute recommended GH as a possible treatment for children with growth failure who have any of the following conditions:
• Turner syndrome,
• Prader-Willi syndrome,
• Chronic renal insufficiency,
• SGA and have growth failure at 4 years,
• SHOX deficiency.
American Association of Clinical Endocrinologists (AACE)
In 2009, the AACE updated its guidelines on GH use in GH-deficient adults and transition patients. (77) Evidence-based recommendations included the following:
• GHD is a well-recognized clinical syndrome in adults that is associated with significant comorbidities if untreated.
• GH should only be prescribed to patients with clinical features suggestive of adult GHD and biochemically proven evidence of adult GHD.
• 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. (78) 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). The statement also mentioned that “psychological counseling is worthwhile to consider instead of or as an adjunct to hormone treatment.”
In 2013, GHRS issued consensus guidelines on rhGH therapy in Prader-Willi syndrome. (79) The following recommendations were made:
• “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.”
In 2016, results from the Growth Hormone Safety Workshop were published in the European Journal of Endocrinology. (80) The workshop was convened by GHRS and other medical societies. The workshop reappraised the safety of rhGH. The position statement concluded:
• After following children and adults for tens of thousands of person-years, the safety profile of rhGH 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 2016, the AAP published guidelines on the evaluation and referral of children with signs of early puberty. (81) The use of GnRH analogues was discussed as treatment options, but GH as a treatment option was not discussed.
In 1997, the Academy published a recommendation on patient selection criterion for children with short stature not associated with classic GHD (82):
• “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
Growth Hormone Deficiency (GHD)
For individuals who have proven 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 improves 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.
Short Stature due to Prader-Willi Syndrome
For individuals who have short stature due to Prader-Willi syndrome who receive human GH, the evidence includes RCTs and a cohort study. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. Several RCTs have found improvements in height, body mass index, head circumference, and motor development in children with Prader-Willi syndrome treated with GH. One RCT reported that GH treatment continued to benefit individuals with Prader-Willi syndrome who had attained adult height, by significantly lowering fat mass and increasing lean body mass. GH treatment was not found to significantly affect problem behavior or total intelligence quotient (IQ). 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.
Short Stature due to Chronic Renal Insufficiency
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.
Short Stature due to Turner Syndrome
For individuals who have short stature due to Turner syndrome who receive human GH, the evidence includes RCTs and observational studies. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. RCTs and observational studies have found that GH therapy increases height outcomes (e.g., final height, height velocity) and positively affects craniofacial development in children with short stature and craniofacial complex 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.
Short Stature due to Noonan Syndrome
For individuals who have short stature due to Noonan syndrome who receive human GH, the evidence includes a systematic review of a controlled trial and 5 uncontrolled studies. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. While the studies in the systematic review were generally of low quality and included only 1 trial comparing patients receiving GH with patients receiving no treatment, reviewers 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.
Short Stature due to Short Stature Homeobox-Containing Gene (SHOX) Deficiency
For individuals who have short stature due to SHOX deficiency who receive human GH, the evidence includes an RCT and an observational long-term study. 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 vs no GH treatment. The long-term study reported that after 4 to 6 years of GH treatment, patients with SHOX deficiency may attain near-adult height. 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 identified. 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, RCTs, and a systematic review with meta-analyses. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. A systematic review and meta-analysis found significant improvements in lean body mass with GH therapy versus placebo; several studies found improvements in quality of life. An RCT with a large sample size reported 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.
Short Bowel Syndrome (SBS) with Specialized Nutritional Support
For individuals who have SBS 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 other studies found improved intestinal absorption in 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.
Small for Gestational Age (SGA) Children
For individuals who are 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 in SGA children resulted in significantly greater adult height compared with no treatment; however, the clinical significance of the height difference between the study groups is unclear. 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.
Altered Body Habitus Related to Antiretroviral Therapy for HIV Infection
For individuals who have altered body habitus related to antiretroviral therapy for HIV infection who receive human GH, the evidence includes case series and an RCT. Relevant outcome are functional outcomes, quality of life, and treatment-related morbidity. The RCT measured the effect of low-dose GH on intermediate outcomes (inflammation markers). 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.
Children with Idiopathic Short Stature (ISS)
For individuals who have 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.
Children with “Genetic Potential”
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 GnRH, the evidence includes a systematic review, an RCT, and a comparative case series. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. While the systematic review included RCTs and controlled trials, only 1 RCT and 4 controlled trials provided data for the meta-analyses of final height, difference in final height and targeted height, and height gain. The meta-analyses reported statistically significant gains of several centimeters for patients who received the combination therapy for at least 1 year compared with patients receiving GnRH alone. However, no studies have reported on the impact of short stature on functional or psychological outcomes in this population. The evidence is insufficient to determine the effects of the technology on health outcomes.
Older Adults with Age-Related GHD
For individuals who are older adults with age-related GHD who receive human GH, the evidence includes a systematic review (Blue Cross Blue Shield Association Technology Evaluation Center Assessment). Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. The 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.
Cystic Fibrosis (CF)
For individuals who have 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. The RCTs were heterogenous and reported various outcomes. None of the systematic reviews pooled results for outcomes such as frequency of intravenous antibiotic treatment, quality of life, and bone fracture. The single pooled outcome (number of hospitalizations) was significantly lower in patients receiving GH therapy versus no treatment or placebo. Across the trials, GH was found to improve intermediate outcomes such as height and weight; however, clinically meaningful outcomes relating to lung function were not consistently improved with GH. The evidence is insufficient to determine the effects of the technology on health outcomes.
For All Other Indications
For individuals who have other indications, (e.g., constitutional growth delay, counter the effects of aging/advanced age/symptoms of aging, anabolic therapy (except for AIDS), glucocorticoid-induced growth failure, short-stature due to Down’s syndrome, intrauterine growth retardation, obesity, idiopathic dilated cardiomyopathy, juvenile idiopathic- or chronic- arthritis, or inflammatory bowel disease) who receive human GH, the evidence is lacking. Relevant outcomes include functional outcomes, quality of life, and treatment-related morbidity and remain under investigation. The evidence is insufficient to determine the effects of the technology on health outcomes.
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|7/15/2018||Document updated with literature review. The following was added in Coverage for patients with Prader-Willi syndrome: 1) With associated growth failure due to Prader-Willi syndrome, who do not have the following contraindications: history of upper airway obstruction or sleep apnea or severe respiratory impairment; and NOTE 11: Sleep studies are recommended prior to initiation of GH therapy for obese pediatric patients with Prader-Willi syndrome. If there are signs that upper airway obstruction and sleep apnea could occur, GH should not be administered. If during treatment, patients develop signs of upper airway obstruction or new sleep apnea, treatment should be interrupted. References 1-3, 8, 22-24, 29, 34, 36, 41, 58, and 64 added. Title changed from Growth Hormone.|
|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|