Archived Policies - Prescription Drugs
Growth Hormone (GH)
Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, Hayes, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.
This is not an all inclusive listing of all growth hormone preparations. Refer to the U.S. Food and Drug Administration (FDA) for all labeled indications of those growth hormones not listed on this policy.
ALERT: All self-injectable medications are administered under the pharmacy benefit.
Growth hormone (GH) therapy is addressed by indications and when the following specific criteria are met (see table below), GH therapy may be considered medically necessary when:
• There are FDA approved label indications; or
• The FDA has granted an Orphan Drug Designation to the drug; or
• There is an off-label listing within a standard reference compendia (such as the American Hospital Formulary Service Drug Information [AHFS DI] or the Thompson Micromedex Drug Dex Compendium [Drug Dex]).
MEDICALLY NECESSARY TABLE
If the FDA approved indication is:
Then the criteria for review includes the following for medically necessary consideration:
Growth hormone (GH) deficiency (GHD), in children
• Failed TWO provocative GH stimulation tests, each with peak value < 10 ng/ml. Testing can be done with growth hormone releasing hormone (GHRH), arginine, insulin, L-dopa, clonidine, or glucagon); OR
• Documentation of proven GHD resulting from either 1) a destructive lesion of the pituitary, 2) a medical treatment, including but not limited to ablative pituitary radiation or surgery, 3) central nervous system pathology; 4) genetic defect (Refer to Turner’s syndrome, Prader-Willi syndrome, or Noonan’s syndrome below); or 5) trauma.
Supportive documentation for children with GHD:
• Documentation of growth velocity under 5.0 cm/year with documentation of height at least 2.0 standard deviations (SD) below mean over one year or more or more than 1.5 SDs sustained over two years; and
• Bone age as determined by standard x-ray techniques to be two years or more behind chronological age.
NOTE: 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: 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; AND
• Serum creatinine is greater than 1.5 mg/dL, or a creatinine clearance is 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: In pediatric patients with chronic renal failure undergoing transplantation, GH therapy is discontinued at the time of transplant or when the growth velocity is less than 2 cm per year, when epiphyseal fusion has occurred, or when the height reaches the 5th percentile of adult height.
GHD, in adults
• Failed TWO provocative GH stimulation tests, each with peak value < 5 ng/ml. Testing can be done with insulin and one of the GHRH preparations, arginine, L-dopa, clonidine, or glucagon; OR
• Documentation of proven GHD resulting from either 1) a destructive lesion of the pituitary; 2) a medical treatment, including but not limited to ablative pituitary radiation or surgery; 3) central nervous system pathology; 4) genetic defect; 5) low concentration of insulin-like growth factor-1 (IGF-1); or 6) trauma.
NOTE: 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: 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: 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: 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: When a diagnosis of GHD is established for an adult, and therapy with GH is initiated, documentation may be requested at one to two year intervals to demonstrate that the patient is obtaining measurable clinical benefit from GH therapy.
NOTE: A physician should consider a trial of withdrawal of GH therapy for patients who do not have demonstrated clinical benefit.
Acquired immunodeficiency syndrome (AIDS) wasting
• Weight loss greater than 10% of baseline weight (refer to NOTE below) that cannot be explained by a concurrent illness other than human immunodeficiency virus (HIV) infection; AND
• Patient is on concurrent antiviral medications.
NOTE: GH therapy is discontinued when the loss is less than 10% of baseline weight loss.
Associated growth failure.
Associated growth failure.
Associated growth failure.
Severe burns, in children
• 3rd degree burns to prevent growth delay, when the treatment begins during acute hospitalization; AND
• Up to one year after the 3rd degree burn, because scar tissue may interfere with growth.
Severe burns, in adults
3rd degree burns requiring promotion of wound healing.
Short bowel syndrome
Treatment with specialized nutritional support in conjunction with optimal management of short bowel syndrome, including dietary adjustments, enteral feedings, parenteral nutrition, and fluid and micronutrient supplements.
NOTE: For additional discussion of short bowel syndrome, see Medical Policy MED201.021, Intestinal Rehabilitation Therapy.
All label and off-label uses of any FDA approved drugs not included in the above medical necessity table are considered not medically necessary OR experimental, investigational and/or unproven as outlined in the tables below when:
• The FDA has determined its use to be contraindicated for a specific condition; or
• The off-label uses cannot be validated by standard reference compendia or peer reviewed literature.
NOT MEDICALLY NECESSARY TABLE
If the FDA approved indication is:
Then the explanation for not medically necessary is:
Small for gestational age (SGA)
• Pediatric patients born SGA who fail to show catch up growth by age 2; as there are no established criteria for SGA or catch-up growth (refer to NOTE below).
NOTE: 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: The American Academy of Pediatrics (AAP) has pointed out that there will always be a population of individuals considered short based on the normal distribution of height, regardless of how the bell-shaped curve may be altered by GH therapy. The American Association of Clinical Endocrinologists and the Growth Hormone Research Society have defined “short-stature” as a height more than 2 SDs below the mean for age and sex. The FDA-approved indication is for children with a height SD of -2.25 below the mean. Using this proposed definition, approximately 1.2% of all children would be defined as having ISS.
• Patients with partial GHD, as these patients do not meet the criteria required for GHD.
• Further lab testing of children without classic GHD to diagnose partial GHD, or other abnormalities of GH secretion or bioactivity, is considered not medically necessary.
NOTE: 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: This includes overnight hospitalization of children for testing of spontaneous GH secretion.
Experimental, Investigational and/or Unproven Table
All Other Indications
Experimental, investigational and/or unproven indications for GH therapy include, but are not limited to, the following:
• Constitutional delay (lower than expected growth percentiles compared with their target height percentiles and delayed skeletal maturation when growth velocities and rates of bone age advancement are normal);
• In conjunction with gonadotropin releasing hormone (GnRH) analogues as a treatment of precocious puberty;
• GH therapy in older adults to counter the effects of aging (without proven GHD);
• Anabolic therapy (except for AIDS), provided to counteract acute or chronic catabolic illness (e.g., surgery outcomes, trauma, cancer, chronic hemodialysis, chronic infectious disease) producing catabolic (protein wasting) changes in both adult and pediatric patients;
• Anabolic therapy to enhance body mass or strength for professional, recreational, or social reasons;
• Glucocorticoid-induced growth failure;
• Short-stature due to Down’s syndrome;
• Intrauterine growth retardation;
• Treatment of altered body habitus (e.g., buffalo hump, lipodystrophy [fat mal-distribution]) associated with antiviral therapy in HIV infected patients;
• Treatment of obesity;
• Treatment of cystic fibrosis (CF);
• Treatment of idiopathic dilated cardiomyopathy;
• Treatment of juvenile idiopathic- or juvenile chronic-arthritis;
• Treatment of advanced age or symptoms of aging;
• Treatment of inflammatory bowel disease; OR
• Treatment of children with “genetic potential” (i.e., lower than expected height percentile based on parents’ height).
The following diagnostic tests for GHD are considered experimental, investigational and/or unproven:
• 24 hour continuous monitoring of GH levels, OR
• Serum levels of insulin-like growth factors (IGF or IGF-1) or insulin-like growth factor-binding protein (IGFBP).
NOTE: Refer to Medical Policy RX501.065 for coverage for Mecasermin Recombinant (Increlex ™ or Iplex/iPLEX ™), which is a recombinant insulin-like human growth factor.
Human growth hormone (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,
• Extrapituitary tumor,
• Sarcoidosis, and/or other infiltrating disorders, or
GHD in children is manifested primarily by short stature. In adults, as well as in some children, other abnormalities associated with GHD are often evident. These include body composition, higher levels of low-density lipoprotein (LD) cholesterol, lower bone density, and a decreased self-reported quality of life compared with healthy peers. Some evidence also suggest that there may be increases in cardiovascular disease and overall mortality, but it is less clear whether GHD is causative for these outcomes.
A major point of controversy is 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. In practical fact, 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.
However, 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.
Beginning in 1985, recombinant GH (rhGH or somatropin) or recombinant DNA (rDNA) origin has been marketed for a variety of FDA-labeled indications. rhGH and rDNA may be used interchangeably. rDNA is also proposed for various non-labeled or off-labeled indications such as cystic fibrosis (CF), treatment of older adults without documented GHD, or fat-maldistribution during human immunodeficiency virus (HIV).
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 U.S. Food and Drug Administration (FDA) approved clinical indications.
Somatropin recombinants and/or somatropin rDNA origin preparations:
In 2001, Genotropin® received an FDA-labeled indication for treatment of pediatric patients born small for gestational age (SGA) who fail 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, FDA approved a recombinant human growth hormone 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 was the first indication that is based on short stature alone, without an underlying etiology. Additional FDA-labeled indications include treatment of children with Prader-Willi syndrome, Turner syndrome, and ISS. Treatment of adults includes either adult-onset or childhood onset GHD.
As with Genotropin®, Humatrope® has been FDA-approved for pediatric patients. Pediatric Patients: Treatment of children with short stature or growth failure associated with growth hormone (GH) deficiency, Turner syndrome, ISS, SHOX (short stature homeobox) deficiency, and failure to catch up in height after SGA birth. The SHOX gene provides instructions for making a protein that regulates the activity of other genes. On the basis of this role, the SHOX protein is called a transcription factor. The SHOX gene is part of a large family of homeobox genes, which act during early embryonic development to control the formation of many body structures. Specifically, the SHOX gene is essential for the development of the skeleton. It plays a particularly important role in the growth and maturation of bones in the arms and legs. Humatrope® has been FDA-approved for adult patients as a treatment for childhood-onset or adult-onset GHD.
Beginning in 2000, Norditropin® had been FDA-approved and was indicated for the long-term treatment of children who have growth failure due to inadequate secretion of endogenous growth hormone. Currently, the FDA-labeled indications include treatment of children with growth failure due to growth hormone deficiency (GHD), short stature associated with Noonan syndrome, short stature associated with Turner syndrome and short stature born SGA with no catch-up growth by age 2 to 4 years. For adult, treatment with either adult-onset or childhood onset GHD has been FDA-approved.
Nutropin® 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 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® 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® 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 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 has not been changed since the 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 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™ is indicated for the treatment of short bowel syndrome in patients receiving specialized nutritional support. It is recommended that Zorbtive™ therapy be used in conjunction with optimal management of short bowel syndrome. Specialized nutritional support may consist of a high carbohydrate, low-fat diet, adjusted for individual patient requirements and preferences.
This policy was created in 1990 based on the U.S. Food and Drug Administration (FDA) –approved labeled indications and routinely updated with literature searches, particularly for off-label use, with the most recent update including searches in the MedLine database and standard reference compendia’s through December 2014. The following discussion focuses on the most controversial aspects of growth hormone (GH) use.
Outcome Measures in Growth Hormone Research
The most common outcome measure reported in growth hormone (GH) research is change in height. For some situations, such as in patients with documented growth hormone deficiency (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 not sufficient evidence to establish that short stature is associated with substantial impairments in psychological functioning or quality of life, nor is there evidence that increases in height improve these parameters. Similarly, improvements in other measures of body composition such as muscle mass or 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 such as functional status, quality of life, or disease-specific clinical outcomes, are necessary to demonstrate an improvement in health outcomes.
Safety of GH Treatment
Adverse effects (AEs) can occur with GH treatment. In children, increased rates of skeletal problems such as worsening of scoliosis can occur in association with a rapid growth spurt. In adults, arthralgias, edema, and carpal tunnel syndrome are common. Less common AEs include pancreatitis and gynecomastia. (1, 2)
There is concern that GH treatment may increase the rate of malignancy, particularly de novo leukemia in patients without risk factors. To date, there is insufficient evidence of a causative relationship between GH treatment and malignancy rates. The largest study published to date on the association of GH treatment with malignancy includes data on 54,996 included in a postmarketing surveillance registry established by Genentech Inc. (3) The most common indications for GH use among children in the database were idiopathic GHD (42.5%), idiopathic short stature (17.8%), organic GHD (15.2%), and Turner syndrome (9.3%). As of January 1, 2006, a total of 4084 AEs (6.2%), including 1559 (2.4%) serious adverse events (SAEs) and 174 (0.3%) deaths, had been reported. Investigators assessed 19 of 174 deaths (11% of deaths) as related to GH treatment. Twelve of the 19 GH-associated deaths were due to neoplasms (0.1% of children in the registry), and the other 7 deaths were each due to a different cause. Overall, intracranial malignancies of nonpituitary origin were reported in 243 patients; 44 were new-onset malignancies. In addition, extracranial malignancies, including leukemia, were reported in 87 patients; 63 were new-onset extracranial malignancies. The authors reported that 36 new-onset malignancies (intracranial and extracranial combined) occurred in individuals without risk factors; 29 of the 36 cases were confirmed as being enrolled in the registry. The rate of new-onset malignancy did not exceed the rate expected in the general population (standard incidence ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.61). This study lacked a concurrent comparison with untreated patients to compare actual rates of malignancy and other adverse events.
In addition, a 2014 study did not find an increased risk of de novo malignancies in GH-treated patients who survived childhood cancer for at least 5 years. (4) The study included 12,098 patients in the U.S. and Canada; 338 (2.8%) were verified users of GH treatment. Sixteen of 338 (4.7%) of GH-treated survivors and 203 (1.7%) non-GHC-treated survivors developed cancers of the central nervous system; the difference between groups was not statistically significant.
Several publications on the safety of GH therapy used French registry data and vital statistics. A 2012 analysis of long-term mortality after GH treatment was conducted by Carel et al. (5) A total of 6928 children were included in the study. Indications for GH therapy included idiopathic isolated GHD (n=5162), neurosecretory dysfunction (n=534), idiopathic short stature (n=871), and born small for gestational age (n=335). The mean dose of GH used was 25 mg/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 of the 6558 individuals (1.42%) had died. The mortality rate was significantly higher in patients treated with GH than the number that would be expected on the basis of year, sex or age (standardized mortality ratio, 1.33; 95% CI, 1.08 to 1.64). Cox survival analysis found that male sex and higher dose of GH were independent predictors of mortality risk. 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 vs 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. (6) This analysis included 6874 children with idiopathic isolated GHD or short stature; mean length of follow-up was 17.4 years. There were 11 (0.16%) validated cases of stroke and the mean age at the time of stroke was 24 years. Risk of stroke was significantly higher in adults who had used GH than in general population controls. Stroke risk was also compared with general population controls. Standard incidence ratios were 2.2 (95% CI, 1.3 to 3.6) compared with registry data from Dijon and 5.3 (95% CI, 3.0 to 8.5) using Oxford registry data. The increased risk was largely for hemorrhagic stroke (8/11 cases), and this elevated risk persisted when the 3 patients who had been small for gestational age were excluded from the analysis. In both of the previous 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.
Once a true GHD has been established in association with clinical symptoms of GHD, there is a compelling rationale for treatment with exogenous GH. There are also randomized controlled trials (RCTs) that support the benefits of GH replacement in terms of increasing height and alleviating secondary effects of GHD. A few representative trials are discussed next.
GHD in Children
In children with GHD, treatment increases growth velocity and final height. Root et al. followed approximately 20,000 children for a period of 9 years as part of the National Cooperative Growth Study. (7) Growth velocity improved compared with pretreatment values, and this improvement was maintained for at least 4 years. For children who were treated for at least 7 years, there were improvements in the mean height standard deviation score (SDS) that ranged from 1.3 to 2.5, depending on the specific underlying condition. If treatment is started at an early age, most children can achieve a final height close to that expected from parental height. In a study of 1258 patients in the Pfizer International Growth Database, the standard deviation (SD) for differences between the final height achieved and the midrange of predicted height from parental values ranged between -0.6 and +0.2, depending on the specific underlying condition.(8)
GHD in Adults
In adults with GHD, there is evidence from RCTs that treatment leads to increases in lean body mass and decreases in body fat. (9) Meta-analyses of RCTs have shown evidence for increases in muscle strength and exercise capacity, although this was not a robust finding across all studies. (10, 11) There is also evidence from meta-analyses that GH therapy is associated with increased bone mineral density (BMD) in adults with GHD. (12, 13) For example, a 2014 meta-analysis by Barake et al. identified 9 placebo-controlled RCTs with at least 1-year follow-up on the effect of daily GH therapy on BMD.13 Analysis of RCT data found a statistically significant increase in BMD of the lumbar spine and femoral neck in patients with GHD who received GH therapy for more than 2 months. Change in BMD ranged from 1% to 5% at the spine and 0.6% to 4% at the femoral neck. A limitation of the Barake analysis is that data were not available on fracture rates, a clinically important outcome. The evidence on other outcomes such as quality of life, lipid profiles, cardiovascular disease, and total mortality is not consistent and is insufficient to determine whether these outcomes are improved with treatment. (14-17)
Growth Failure due to Prader-Willi Syndrome
Most children with Prader-Willi syndrome have hypothalamic dysfunction and are GH deficient. Use of human growth hormone (HGH) for children with growth failure due to Prader-Willi syndrome is an FDA-approved indication. 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 GH, nor were results reported separately for those with or without GHD. Information from the product label indicates that the height SDS for Prader-Willi syndrome children in the clinical studies was -1.6 or less (height was in the 10th percentile or lower).
Several studies have shown patient improvements with use of GH. For example, a 2008 RCT published by Festen et al. included 42 infants and 49 prepubertal children (age range, 3-14 years) and found that GH treatment significantly improved height, body mass index, head circumference, and body composition. (18) In 2012, the investigators published cognitive outcomes in children participating in this trial. (19) During the 2-year randomized study, the 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. (20) This was a 2-year single-blind trial that included 22 children newly diagnosed with Prader-Willi syndrome (mean age, 12.9 months). 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 the finding that GH had statistically significant interaction effects on a model predicting motor development age using the Alberta Infant Motor Scale.
According to the drug prescribing information, GH therapy use has been associated with sudden death in children with Prader-Willi syndrome. (21) These deaths occurred among children who were severely obese or had severe respiratory impairment; these are now considered to be contraindications to GH treatment use. Because of this, many specialists now recommend sleep studies and correction of underlying airway obstruction before initiating GH treatment in these patients.
For adults with Prader-Willi syndrome, the benefits of GH treatment are less apparent, and treatment of adults with Prader-Willi syndrome is not an FDA-approved indication for GH (Genotropin). In 2012, Sode-Carlsen et al. in Scandinavia published an RCT evaluating GH therapy in 46 adults with genetically verified Prader-Willi syndrome. (22) Patients were randomized to receive 12 months of GH treatment or placebo. The authors reported a number of outcomes related to body composition and laboratory test results; they did not specify a primary outcome. In addition, the authors primarily reported within-group outcomes. For example, in the GH-treated group, after 1 year, lean body mass increased a mean of 2.25 kg (p=0.005 vs baseline), and fat mass decreased by a mean of 4.2 kg (p<0.001 vs baseline). In the same time period, there was no significant change in lean body mass in the placebo group and a significant increase (p<0.001) in fat mass (change in kg was not reported for the placebo group). During the 12-month treatment period, no significant changes were found in either group on other variables including in levels of high-density lipoprotein?cholesterol or triglycerides, peak expiratory flow, fasting glucose, fasting insulin and physical function. However, the level of low-density lipoprotein?cholesterol decreased significantly more in the GH-treated compared with control group (mean difference [MD], 0.27 mmol/L, p=0.047). This study presents insufficient evidence that GH therapy is effective for improving health outcomes in adults with Prader-Willi syndrome.
For patients with documented GHD and clinical manifestations such as short stature, GH replacement has been shown to improve growth velocity and final height achieved. In addition, it can ameliorate the secondary manifestations of GHD seen primarily in older children and adults. Therefore, GH replacement may be considered medically necessary for these indications. For children with Prader-Willi syndrome and growth failure, GHD is assumed, and GH replacement may be considered medically necessary without documentation of GHD.
Conditions without GHD
Children with Short Stature Associated with Chronic Renal Insufficiency
In 2013, Wu et al. published a meta-analysis of RCTs evaluating the impact of GH therapy on height outcomes following renal transplant in children age 0 to 18 years. (23) Five trials with a total of 401 participants met the review’s inclusion criteria (RCTs including renal allograft recipients between 0-18 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 growth hormone 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 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. (24) To be included in the review, trials needed to include children 18 years-old or younger who were diagnosed with chronic kidney disease and were predialysis, on dialysis, or posttransplant. In addition, trials needed to compare GH treatment with placebo, no treatment or a different GH regimen and needed to include height outcomes. A total of 7 RCTs with 809 children met the review criteria. Study entry criteria varied, e.g., ranging from less than 3rd percentile for chronological age to less than 50th percentile for chronological 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).
An example of an individual RCT is the trial by Hokken-Koelega et al. conducted in the Netherlands. This was a double-blind placebo-controlled crossover trial in 20 prepubertal children with severe growth retardation and chronic renal failure. (25) Entry criteria included height velocity less than the 25% percentile for chronological 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 compared 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. (26) 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 that was within the normal range for girls and boys, and GH therapy did not result in significant effects on parathyroid hormone concentration, and there were no radiologic signs of renal osteodystrophy.
Altered Body Habitus Related to Antiretroviral Therapy for HIV Infection
There has been research interest in the use of GH to treat the altered body habitus that may be a complication of antiretroviral therapy for HIV infection. Body habitus changes, also referred to as the fat redistribution syndrome, include thinning of the face, thinning of the extremities, truncal obesity, breast enlargement, or an increased dorsocervical fat pad ("buffalo hump"). (27) However, there is minimal published literature regarding the use of GH for this indication. The literature is dominated by letters to the editors and small case series. The largest case series was reported by Wanke et al. who treated 10 HIV-infected patients with fat redistribution syndrome with GH for 3 months. (28) The authors reported improved waist/hip ratio and mid-thigh circumference.
Short stature is almost universal in Turner syndrome. 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). Unlike Prader-Willi syndrome, GHD is not seen. FDA-approvals for GH were based on the results of RCTs that included final adult height as the outcome. For example, a group of patients with Turner syndrome given Humatrope at a dosage of 0.3 mg/kg/wk for a median of 4.7 years achieved a final height of 146.0±6.2 cm (57.5±2.25 inches) compared with an untreated control group who achieved a final height of 142.1±4.8 cm (56±2 inches). (29)
In 2007, a Cochrane review identified 4 RCTs (total N=365) evaluating GH for treating Turner syndrome. (30) Studies included children who had not yet achieved final height, treated children for at least 6 months, and compared GH with placebo or no treatment. Only 1 trial reported final height, so findings on this outcome could not be pooled. A pooled analysis of 2 trials found that short-term growth velocity was greater in treated than untreated children (MD=3 cm/y; 95% CI, 2 to 4 cm/y).
Short Stature Due to Noonan Syndrome
In 2007, the FDA approved use of GH (Norditropin) for treatment of short stature in children with Noonan syndrome. This approval was based on a comparative study of 21 children that showed improvement in height and growth velocity in those with short stature due to Noonan syndrome. (31)
Children with Short Stature Due to Short Stature Homeobox-Containing Gene Deficiency
Treatment of children with short stature due to short stature homeobox-containing gene (SHOX) deficiency is an FDA-approved indication for GH therapy (Humatrope). (29) A 2010 Health Technology Assessment on GH treatment of growth disorders in children conducted a systematic review and identified 1 RCT evaluating GH therapy for children with short stature due to SHOX. (32) This industry-sponsored open-label multicenter study was published by Blum et al.in 2007. (33) It included 52 prepubertal children age at least 3 years who had SHOX deficiency. Height requirements were less than the 3rd percentile of the local reference range or less than 10th percentile with height velocity less than the 25th percentile. Participants were randomized to receive 2 years of GH treatment (n=27) or usual care (n=25). The primary outcome was first-year height velocity. Fifty-one of 52 patients completed the study. The first-year height velocity (cm/y) was 8.7 cm (SD=0.3) in the GH therapy group and 5.2 (SD=0.2) in the untreated group; the difference between groups was statistically significant (p<0.001). Height gain over the 2-year treatment period was 16.4 (SD=0.4) cm in the treatment group and 10.5 (0.4) cm in the untreated group (p<0.001). No serious adverse effects (SAEs) were reported for either of the 2 groups of patients.
Treatment of Severe Burns
A Cochrane systematic review published in 2012 included RCTs evaluating the impact GH therapy on the healing rate of burn wounds. (34) Thirteen trials were identified that compared GH therapy with another intervention or to placebo. Six of these included only children and 7 involved only adults. Twelve of the 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 compared with placebo (MD=-9.07 days; 95% CI, -4.39 to -13.76). The authors 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 (risk ratio [RR], 0.53; 95% CI, 0.22 to 1.29). The mortality analysis was likely underpowered; the total number of deaths was 17. A pooled analysis of 3 studies involving adults found significantly shorter hospital stays in patients who received GH therapy compared with placebo (MD=12.55 days; 95% CI, -17.09 to -8.00). In another pooled analysis, there was a significantly higher incidence of hyperglycemia in growth hormone-treated patients compared with controls (RR=2.65; 95% CI, 1.68 to 4.16).
One study that measured mortality was published by Knox et al. (35) This was an RCT in 54 adult burn patients who survived the first 7 postburn days. Those patients showing difficulty with wound healing were treated with recombinant human GH (rhGH) and compared with those healing at the expected rate with standard therapy. Mortality of rhGH-treated patients was 11% compared with 37% not receiving rhGH (p=0.027). Infection rates were similar in both groups. Moreover, Singh et al. studied 2 groups of patients (n=22) with comparable third-degree burns; those who received GH had improved wound healing and lower mortality (8% vs. 44%). (36) Another placebo-controlled trial found no benefit to GH with regard to length of hospitalization in 24 adult patients with severe burns. (37)
Prevention 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. (38) 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. (39)
GH Therapy in Conjunction with Optimal Management of Short Bowel Syndrome
Short-bowel syndrome is experienced by patients who have had half or more of the small intestine removed with resulting malnourishment because the remaining small intestine is unable to absorb enough water, vitamins, and other nutrients from food. The FDA-label for Zorbtive® indicates that GH has been shown in human clinical trials to enhance the transmucosal transport of water, electrolytes, and nutrients. FDA-approval for Zorbtive® was based on the results of a randomized, controlled, phase 3 clinical 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 the treatment locations (inpatient vs outpatient) identified.
A 2010 Cochrane review identified 5 RCTs evaluating GH therapy for treating short-bowel syndrome. (40) Studies evaluated GH with or without glutamine treatment. The primary outcome was change in body weight. A pooled analysis of 3 small trials (total N=30) found a statistically significant difference in weight change when patients were treated with GH or placebo (MD=1.66 kg; 95% CI, 0.69 to 2.63; p<0.001).
Several published studies have also demonstrated improved intestinal absorption in short-bowel syndrome patients receiving parenteral nutrition. (41, 42) However, studies have noted that the effects of increased intestinal absorption are limited to the treatment period. (42, 43) Specialized clinics may offer intestinal rehabilitation for patients with short-bowel syndrome; GH may be one component of this therapy. Inpatient intestinal rehabilitation is considered separately in another policy.
Small for Gestational Age (SGA) Children
A meta-analysis of RCTs evaluating GH treatment for children born SGA was published in 2009. (44) Four trials with a total of 391 children met the eligibility criteria (birth height or weight <2 SDS, initial height <2 SDS). The GH dose ranged from 33 to 67 mg/kg in the RCTs, and the 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. The adult height in the treated group was significantly higher than that of controls (MD=0.9 SDS [5.7 cm]; p<0001). There was no difference in adult height between the 2 doses of 33 and 67 mg/kg/d. The authors commented 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 minimal data regarding 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 earlier, data are inadequate to document that short-stature youths have either low self-esteem or a higher than average number of behavioral or emotional problems.
For both small for gestational age children and short-stature children, an additional strategy to achieve target adult heights is to combine GH therapy with gonadotropin hormone releasing (GnRH) analogs, which prolong the prepubertal growth period. The combined therapy is intended to increase the critical pubertal height gain by delaying the fusion of the epiphyseal growth plates, thus prolonging the period during which GH is active. This therapy has been suggested for children who are considered short when they enter puberty. (45-47)
Children with Idiopathic Short Stature (ISS) (i.e., without documented GHD or underlying pathology)
Impact of GH Treatment on Adult Height of Children with ISS
Several meta-analyses have been published. Most recently, Deodati and Cianfarani identified 3 RCTs and 7 non-RCTs. (48) To be included in the meta-analysis, studies needed to include prepubertal children with initial short stature (>2 SD below the mean) and peak GH response greater than 10 mg/L. In addition, participants needed to have no previous GH therapy and no comorbid conditions that could impair growth. Adult height was defined as a growth rate of less than 1.5 cm/y or bone age was 15 years in females and 16 years in adults. The primary efficacy outcome was the difference between groups in adult height; this was measured as an SDS (also known as a z score). The investigators considered a mean difference in height of more than 0.9 SDS (≈6 cm) to be a satisfactory response to GH therapy. Only 1 of the RCTs was placebo-controlled, and that study had a high dropout rate (40% in the treated group, 65% in the placebo group).
In the 3 RCTs (total N=115), the mean adult height (primary efficacy outcome) was -1.52 SDS for treated children and -2.30 SDS for untreated children. The difference between groups significantly favored the treated group (MD=0.65 SDS [≈4 cm]; 95% CI, 0.40 to 0.91 SDS; p<0.001). The mean adult height in the 7 non-randomized studies was -1.7 SDS for treated children and -2.1 SDS for untreated children. The MD between groups was 0.45 SDS (3 cm) (95% CI, 0.18 to 0.73) and was statistically significant favoring the treated group (p<0.001). Although GH treatment resulted in a statistically significant increase in adult height in the treated group, according to the a priori definition of a satisfactory response, the difference was not clinically significant. Moreover, there was a lack of high-quality placebo-controlled RCTs.
In 2009, a Cochrane review of RCTs by Bryant et al. evaluating GH therapy for ISS in children and adolescents was published. (49) A total of 10 RCTs met eligibility criteria, which included 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 needed to compare GH treatment with placebo or no treatment and provide GH treatment for at least 6 months. Three studies were placebo controlled, and the other 7 compared GH therapy with no treatment. Unlike the Deodati and Cianfarani review previously described studies were not required to report final adult height. Nine of 10 studies in the Cochrane review were short term and reported intermediate outcomes. A pooled analysis of 3 studies reporting growth velocity at 1 year found a statistically significantly greater growth velocity in treated compared with 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 their 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.
Recent systematic reviews have found that GH treatment may result in increases in 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 is in the range of 3 to 4 cm, and children treated with GH remain below average in height, with heights that are between 1 and 2 SD below the mean at the end of treatment. These studies do not follow treated patients long enough to determine the ultimate impact of GH on final adult height.
Impact of GH Treatment on Self-Esteem and Quality of Life in Children with Idiopathic Short Stature
Advocates of GH therapy often cite the potential psychosocial impairments associated with short stature. However, several RCTs have addressed this topic, and they have not found 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. (50) Children (mean age, 12.4 years) were randomized to receive GH therapy (n=37) or placebo (n=31) 3 times per week until height velocity decreased to less than 1.5 cm per year. At baseline and then yearly, parents and children completed several psychological instruments including the Child Behavior Checklist (CBCL) and Self-Perception Profile (SPP). No significant associations were found between attained height SDS or change in height SDS and annual changes in scores on the CBCL. There were no significant differences between groups on any CBCL summary scales in years 1 and 2, but in year 4, there were significantly higher scores on the CBCL summary scales in the group receiving GH treatment.
There were no significant differences between groups on the SPP at any follow-up point. In conclusion, short stature in this study was not associated with problems in psychological adaptation or self-concept.
Theunissen et al. in the Netherlands published a trial in 2002 in which 40 prepubertal children with ISS were randomly assigned to GH treatment (n=20) or a control group (n=20). (51)
Parents and children were interviewed at baseline and at 1 and 2 years to obtain information on health-related quality of life (HRQOL) and children’s self-esteem. At the 2-year follow-up, satisfaction with current height was significantly associated with improvement in children’s reported HRQOL, social functioning, and other psychosocial measures. However, satisfaction with height did not differ significantly between the treatment and control groups. The data from this study do not support the hypothesis that GH treatment improves HRQOL in children with ISS.
In 1996, Downie et al. examined the behavior of children without documented GHD who were treated with GH due to idiopathic short stature. (52) Across measures of behavior, including IQ, self-esteem, self-perception, or parental perceptions of competence, there were no significant differences between the control and 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.
RCTs have not found that short stature is associated with psychological problems, in contrast 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.
In light of the published research on the impact of GH on health outcomes for children with ISS, and because this group of children is otherwise healthy and there are potential risks to GH therapy in childhood (see earlier section on Safety), GH treatment for children with ISS is considered not medically necessary.
GH Use in Children with “Genetic Potential” (i.e., lower than expected height percentiles based on parents’ height)
No randomized or nonrandomized studies were identified that evaluated the efficacy, safety, and/or psychosocial impacts of treating this group of children with GH therapy.
GH Therapy in Conjunction with GnRH Therapy as a Treatment of Precocious Puberty
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 analogs to suppress the pituitary gonadal activity, to slow the advancement of bone age, and to improve adult height. Several long-term studies have reported that treatment with GnRH analogs is associated with improved adult height in most cases, particularly in those with the most accelerated bone age progression at treatment onset, the shortest predicted height, and the greatest difference between the target height and the predicted height. (53-55) In contrast, patients with a slowly progressive form in which the predicted height does not change after 2 years of follow-up may not require any treatment. In another subset of patients, GnRH analog therapy may be associated with a marked deceleration of bone growth that may ultimately result in an adult stature that is less than the targeted midparental height. GH may be offered to these patients to achieve the targeted adult height. There have been no RCTs comparing final adult height in those treated with GnRH analogs alone versus GnRH analogs combined with GH therapy, and the largest case series includes 35 patients. Case series suggest that GH is most commonly offered as an adjunct to GnRH analogs when the growth velocity drops below the 25th percentile for chronologic age. (56, 57) A series of comparative case series that have included final adult heights have been reported by the same group of investigators from Italy. This group of investigators is the only one to have reported final adult heights. The most recent reports focus on a group of 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. (56)
Those in the combined group attained a significantly greater adult height (161.2±4.8 cm) than the “control” group (156.7±5.7 cm). This small study is inadequate to permit scientific conclusions. Tuvemo et al. reported on the results of a trial that randomized 46 girls with precocious puberty to receive either GnRH analogs or GnRH analogs in addition to GH. (58) Of interest, all the participants were adopted from developing countries; precocious puberty is thought to be common in such cross-cultural adoptions. Criteria for participation in this trial did not include predicted adult height or growth velocity. After 2 years of treatment, the mean growth and predicted adult height were greater in those receiving combined treatment compared with those receiving GnRH analogs alone. The absence of final height data limits interpretation of this trial.
As noted here, the not medically necessary status of other applications of GH for non-GH deficient short-stature children is based on the absence of a functional impairment associated with a less than predicted final adult height. While these same considerations may apply to using GH therapy as a component of therapy for precocious puberty, the experimental, investigational and/or unproven status of this indication is based on lack of final height data from controlled trials.
GH Therapy in Older Adults
The GH secretion rate decreases by an estimated 14% per decade after young adulthood; mean levels in older adults are less than half those of a young adult. However, mean GH levels in older adults are greater than age-matched adults with diagnosed GHD. Older individuals experience changes in body composition, loss of muscle mass, and decreases in BMD that are similar to changes seen in adults with biochemically verified GHD. Based on these observations, GH therapy has been investigated in older adults without organic pituitary disease. The policy regarding this off-label application is based on a 2001 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment (59), which concluded that there was insufficient evidence of efficacy. It is not possible to prove effectiveness of GH treatment or lack thereof unless otherwise similar groups of treated versus non-treated patients are compared over a sufficient length of time to allow detection of any significantly and clinically different results.
GH Therapy for 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. (60) The authors identified 4 RCTs with a total of 161 participants. All of the studies used daily subcutaneous injection of recombinant GH as the intervention and included a no treatment or placebo control group. The studies all measured pulmonary function and nutritional status. However, due to differences in how these outcomes were measured, study findings were not pooled. Previously, a 2010 systematic review identified 10 controlled trials evaluating GH for treating patients with CF. (61) One study was placebo-controlled, 8 compared GH therapy with no treatment, and the remaining trial compared GH alone with glutamine or glutamine plus GH. In 1 study, patients were treated with GH for 4 weeks and in the other studies, duration of treatment ranged from 6 months to 1 year. There were insufficient data to determine the effect of GH on most health outcomes including frequency of intravenous antibiotic treatment, quality of life, and bone fracture. Data were pooled on 1 outcome, frequency of hospitalizations. In trials with durations of at least 1 year, there was a significantly lower rate of hospitalizations per year in the group receiving GH therapy (pooled effect size, -1.62; 95% CI, -1.98 to -1.26).
One of the RCTs was an industry-sponsored open-label study published by Stalvey et al. in 2012. (62) This study compared GH therapy with no treatment in prepubertal children with CF who were younger than 14 years old. The eligibility criteria included height no more than 10th percentile for age and sex; children with documented GHD were excluded. Participants were treated daily for 12 months and were followed for an additional 6 months. The study included 68 children; 62 (91%) were included in the efficacy analysis, and all but 1 were included in the safety analysis. Annualized height velocity at month 12 was 8.2 cm/y (SD=2.1) in the treatment group and 5.3 cm/y (SD=1.3) in the control group; the difference between groups was statistically significant, p<0.001). Mean height SDS in the treatment group was -1.8 at baseline, -1.4 at 12 months, and -1.4 at 18 months. Mean height SDS in the control group was -1.9 at all 3 time points. Change in mean height SDS from baseline to 12 months was significantly greater in the treatment compared with the control group (p<0.001). Between months 12 and 18 (after treatment ended), the control group remained at the same height SDS, and the treatment group experienced a slight decline (0.1 SDS), but maintained a 0.5 SDS advantage over the control group.
In terms of pulmonary outcomes, the unadjusted rate of change from baseline to 12 months in most variables (7/8 pulmonary test results) did not differ between groups. However, the unadjusted change from 12 months to 18 months (after treatment ended) was significantly greater in the control group than the treatment group in 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 (SD=451) at baseline, 1434 (SD=539) at 12 months, and 1467 (SD=568) at 18 months. This compared with 1400 (SD=495) at baseline, 1542 (SD=510) at 12 months, and 1674 (SD=510) at 18 months in the control group. From baseline to 12 months, the between-group difference in change in the 6-minute walk distance was 26.3 meters (95% CI, -44.8 to 97.4 meters) (p=0.46). Ten children in the treatment group and 9 in the control group were hospitalized for pulmonary exacerbations during the 12-month study period; the difference between groups was not statistically significant. In general, treatment with GH resulted in statistically significant improvement in height SDS but did not significantly improve outcomes associated with cystic fibrosis. A limitation of this study was that it was not blinded; however, this is less of a potential bias in a study like this one that has objective outcomes such as height and hospitalization rate.
GH treatment has been used in numerous conditions where there is not documented GHD. For some of these conditions that are associated with growth failure, such as Turner syndrome, Noonan syndrome, SHOX mutations, short-bowel syndrome, and children with renal insufficiency, there is FDA-approval for GH treatment, there is some clinical trial evidence that treatment leads to improved growth velocity and/or final height, and there is support for use of GH in clinical practice guidelines. The evidence is mixed on use of GH therapy for treating severe burns, with numerous trials and systematic reviews reporting improved healing times. Some, but not all, controlled studies have found improved clinical outcomes, e.g., lower mortality, and/or shorter hospital stay when GH therapy was used. Therefore, GH treatment may be considered medically necessary for these indications.
There are some FDA-approved indications for GH treatment in which there are no associated pathologic disorders. These include pediatric patients born SGA and children with height that is more than 2.25 SD below the age-adjusted mean. For these situations, the use of GH replacement has not been demonstrated to have health outcome benefits other than improved height. Because of this lack of demonstrated health outcome benefits together with the potential for AEs, the use of GH treatment for these patients is considered not medically necessary.
GH treatment for various other indications
Lipodystrophy: Since the use of GH is not FDA approved for this indication, this use remains considered experimental, investigational and/or unproven (21, 29, 31, 73). The coverage statement is unchanged. However, some studies have demonstrated the efficacy of GH treatment to reduce visceral adipose tissue and to improve peripheral fat wasting as part of body habitus changes and metabolic abnormalities commonly observed in HIV patients.
Advanced Aging: Although advanced age or symptoms of aging are not among approved indications for GH therapy, rhGH and various GH-related products are aggressively promoted as anti-aging therapies. Well-controlled studies of the effects of GH therapy in endocrinologically normal elderly subjects report some improvements in body composition and a number of undesirable side effects in sharp contrast to the major benefits of GH therapy in patients with GHD. Since the use of GH is not FDA approved for this indication, this use is considered experimental, investigational and/or unproven (21, 29, 31, 73).
Inflammatory Bowel Disease: Since the use of GH is not FDA approved for this indication, this use remains experimental, investigational and/or unproven. This coverage statement is unchanged. Studies have not clarified patient selection or long-term use during GH treatment of patients with inflammatory bowel disease (21, 29, 31, 73).
Other Indications: GH therapy has been investigated for use in the treatment of idiopathic dilated cardiomyopathy and juvenile idiopathic arthritis. No RCTs were identified to sufficiently demonstrate the appropriateness of GH therapy in these conditions. Since the use of GH is not FDA approved for these indications, their use is considered experimental, investigational and/or unproven (21, 29, 31, 73).
For numerous other indications that are not FDA-approved, there is a variable amount of evidence reporting on the impact of GH replacement on height, but there is a lack of evidence establishing that outcomes other than height are improved. For these conditions, the use of GH treatment is considered experimental, investigational and/or unproven.
Ongoing and Unpublished Clinical Trials
Aromatase Inhibitors, Alone And In Combination with Growth Hormone In Adolescent Boys With Idiopathic Short Stature (ThrasherAI) (NCT01248416) (63): This open-label trial is randomly assigning adolescent boys with idiopathic short stature (≤-2 SD for height) to one of 3 treatment groups: 1) aromatase inhibitors alone; 2) somatropin alone; or 3) combination of aromatase inhibitor and somatropin. Change in height will be assessed at 1 and 2 years. The estimated enrollment is 77 participants, and the estimated date of study completion is October 2017.
Short Stature-Related Distress (NCT01246219) (64): This double-blind placebo-controlled trial is comparing psychological measures in participants with idiopathic short stature who are treated with GH therapy compared with placebo, compared with no treatment and compared with controls of normal height. Idiopathic short stature is defined as more than 2 SD below the average height; boys between the ages of 8 and 13 years will be included. Individuals with mental retardation or psychiatric illness will be excluded. The estimated enrollment will be 120 participants, and the estimated date of study completion is December 2015.
Severe Decrease of Growth Velocity in Children with Anorexia Nervosa. Therapeutic Trial of Growth Hormone (OREX) (NCT01626833) (65): This is a double-blind placebo-controlled trial that is evaluating growth hormone for treating children with clinical anorexia nervosa diagnosed at least 1 year before the study. Growth velocity needs to be documented for at least 18 months before study inclusion. The primary outcome is growth velocity after 1 year of treatment. Expected enrollment is 20 individuals and the expected date of study completion is September 2016.
Practice Guidelines and Position Statements
In 2013, a Growth Hormone Research Society workshop issued consensus guidelines on recombinant GH (rhGH) therapy in Prader-Willi syndrome. (66) The following were among the group’s recommendations:
• “After genetic confirmation of the diagnosis of PWS [Prader-Willi syndrome], rhGH treatment should be considered and, if initiated, should be continued for as long as demonstrated benefits outweigh the risks.”
• “GH stimulation testing should not be required as part of the therapeutic decision-making process in infants and children with PWS.”
• “Exclusion criteria for starting rhGH in patients with PWS include severe obesity, uncontrolled diabetes, untreated severe obstructive sleep apnea, active cancer, and active psychosis.”
• Scoliosis and cognitive impairment should not be considered exclusion criteria.
An Endocrine Society clinical practice guideline on adult growth hormone deficiency (GHD), updated in 2011, includes the following statements (67):
• The Task Force recommends that GH [growth hormone] 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.
In 2010, the National Institute of Health and Clinical Excellence (NICE) in the United Kingdom issued guidance on human growth hormone for growth failure in children. (68) NICE recommends GH as a possible treatment for children with growth failure who have any of the following conditions:
• Growth hormone deficiency,
• Turner syndrome,
• Prader-Willi syndrome,
• Chronic renal insufficiency,
• Small for gestational age and have growth failure at 4 years,
• Short stature homeobox (SHOX) gene deficiency.
In 2009, the American Association of Clinical Endocrinologists issued updated guidelines on growth hormone use in growth hormone-deficient adults and transition patients. (69) Evidence-based recommendations include the following:
• Growth hormone deficiency (GHD) is a well-recognized clinical syndrome in adults that is associated with significant comorbidities if untreated.
• Growth hormone (GH) should only be prescribed to patients with clinical features suggestive of adult growth hormone deficiency and biochemically proven evidence of adult growth hormone deficiency.
• No data are available to suggest that GH has beneficial effects in treating aging and age-related conditions and the enhancement of sporting performance; therefore, the guideline developers do not recommend the prescription of GH to patients for any reason other than the well-defined approved uses of the drug.
In 2008, the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology Workshop published a consensus statement on the diagnosis and treatment of children with idiopathic short stature. (70) Within the working group that developed the statement, the appropriate height below which GH treatment should be considered ranged from -2 to -3 SDS. The optimal age for treatment was thought to be between 5 years and early puberty. The group noted that psychological issues should be considered, e.g., GH therapy should not be recommended for short children who are unconcerned about stature.
In January 1997, the American Academy of Pediatricians published a document that recommended the following patient selection criterion for children with short stature not associated with classic GH deficiency (71):
“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.”
This is a multi-section medical policy and evidence is summarized at the end of each section.
Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.
Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.
The following codes may be applicable to this Medical policy and may not be all inclusive.
J2940, J2941, S9558
ICD-9 Diagnosis Codes
Refer to the ICD-9-CM manual
ICD-9 Procedure Codes
Refer to the ICD-9-CM manual
ICD-10 Diagnosis Codes
Refer to the ICD-10-CM manual
ICD-10 Procedure Codes
Refer to the ICD-10-CM manual
The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.
A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
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25. Hokken-Koelega AC, Stijnen T, de Muinck Keizer-Schrama SM, et al. Placebo-controlled, double-blind, crossover trial of growth hormone treatment in prepubertal children with chronic renal failure. Lancet. Sep 7 1991; 338(8767):585-90.
26. Hokken-Koelega A, Mulder P, De Jong R, et al. Long-term effects of growth hormone treatment on growth and puberty in patients with chronic renal insufficiency. Pediatr Nephrol. Jul 2000; 14(7):701-6.
27. Lo, J.C., Mulligan, K., et al. “Buffalo hump” in men with HIV-1 infection. Lancet (1998 March 21) 351(9106):867-70.
28. Wanke, C., Gerrior, J., et al. Recombinant human growth hormone improves the fat distribution syndrome (lipodystrophy) in patients with HIV. AIDS (1999 October 22) 13(15):2099-13
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33. Blum WF, Crowe BJ, Quigley CA, et al. Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: Two-year results of a randomized, controlled, multicenter trial. J Clin Endocrinol Metab. Jan 2007; 92(1):219-28.
34. Breederveld RS, Tuinebreijer WE. Recombinant human growth hormone for treating burns and donor sites. Cochrane Database Syst Rev. 2012; 12:CD008990.
35. Knox, J., Demling, R., et al. Increased survival after major thermal injury: the effect of growth hormone therapy in adults. Journal of Trauma (1995 September) 39(3):526-30; discussion 530-2.
36. Singh, K.P., Prasad, R., et al. Effect of growth hormone therapy in burn patients on conservative treatment. Burns (1998 December) 24(8):733-8.
37. Losada, F., Garcia-Luna, P.P., et al. Effects of human recombinant growth hormone on donor-site health in burned adults. World Journal of Surgery (2002 January) 26(1):2-8.
38. Hart, D.W., Herndon, D.N., et al. Attenuation of posttraumatic muscle catabolism and osteopenia by long-term growth hormone therapy. Annals of Surgery (2001 June) 233(6):827-34
39. Aili Low, J.F., Barrow, R.E., et al. The effect of short-term growth hormone treatment on growth and energy expenditure in burned children. Burns (2001 August) 27(5):447-52.
40. Wales, P.W., Nasr, A., et al. Human growth hormone and glutamine for patients with short bowel syndrome. Cochrane Database Systematic Review (2010) (6):CD006321.
41. Scolapio, J.S. Effect of growth hormone, glutamine, and diet on body composition in short bowel syndrome; a randomized, controlled study. Journal of Parenteral Enteral Nutrition (1999 November-December) 23(6):309-12; discussion 312-3.
42. Seguy, D., Vahedi, K., et al. Low-dose growth hormone in adult home parenteral nutrition-dependent short bowel syndrome patients: a positive study. Gastroenterology (2003 February) 124(2):293-302.
43. Szkudlarek, J., Jeppesen, P.B., et al. Effect of high dose growth hormone with glutamine and no change in diet on intestinal absorption in short bowel patients: a randomized, double blind, crossover, placebo controlled study. GUT (2000 August) 47(2):199-205.
44. Maiorana, A., and S. Cianfarani. Impact of growth hormone therapy on adult height of children born small for gestation age. Pediatrics (2009 September) 124(3):e519-31.
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46. Saggese, G., Cesaretti, G., et al. Combination treatment with growth hormone and gonadotropin-releasing hormone analogs in short normal girls. Journal of Pediatrics (1995 March) 126(3):468-73.
47. Tanaka, T., Satoh, M., et al. When and how to combine growth hormone with a luteinizing hormone-releasing hormone analogue. ACTA Paediatrica Supplement (1999 February) 88(428):85-8.
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|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:|
|Human Growth Hormone (GH)||07-15-2018||06-14-2019|
|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|