Coverage Policy Manual
Policy #: 1997087
Category: Pharmacy
Initiated: January 1993
Last Review: February 2019
  Growth Hormone, Human

Description:
Human growth hormone (GH), also known as somatotropin, is synthesized in somatotropic cells of the anterior lobe of the pituitary gland. Since 1985 recombinant GH has been marketed (trade names: Humatrope, Nutropin, Somatrem, Genotropin, Nutropin, Saizen, Serostim, Tev-Tropin and Zorbitin) as replacement therapy for for a number of indications. GH is administered intramuscularly or subcutaneously at a dosage of 0.1 IU/kg of body weight to 0.3 IU/kg of body weight a week. This can be divided into the appropriate dose for daily injections six to seven times a week or three times a week.
 
The following are the FDA-approved labeled indications for GH therapy:
    • Children who have growth failure due to an inadequate secretion of normal endogenous growth hormone;
    • Children with chronic renal insufficiency before renal transplant;
    • Children with Turner’s syndrome, i.e.., a 45, XO genotype;
    • Adults with congenital or acquired GH deficiency;
    • Patients with AIDS wasting;
    • For long term treatment of growth failure in children born small for gestational age who fail to manifest catch-up growth by two years of age.
    • Growth failure due to Prader-Willi syndrome.
    • Short stature in non-GHD children.
    • Treatment of short bowel syndrome.
    • Short stature in children with short stature homeobox-containing gene deficiency.
    • Short stature in children with Noonan syndrome.
 
A major point of controversy is what defines "inadequate secretion of normal endogenous growth hormone."  Prior to the availability of biosynthetic GH, GH was rationed to those children with classic growth hormone deficiency as defined by a subnormal response (less than 10 NG/ml) to GH provocation tests. However, the ready supply of GH has created interest in expanding its use to short-statured children without classic growth hormone deficiency (GHD), often referred to as partial GH deficiency, neurosecretory GH dysfunction, constitutional delay in growth and development (CDGD), or idiopathic short stature. "Classic" growth hormone deficiency is suggested when there is an abnormal growth velocity (typically below the 10th percentile) in conjunction with a chronological 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 - selection of patients to be tested, limitations in the laboratory testing for GH, establishment of diagnostic cutoffs for normal vs. 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. Additionally, there are many ethical considerations regarding GH therapy, most prominently appropriate consent when the therapy is primarily requested by the parent due to their psychosocial concerns regarding height.
 
In 2001, Genotropin received a U.S. Food and Drug Administration (FDA)-labeled indication for treatment of pediatric patients born small for gestational age who fail to show catch-up growth by age 2 years. Most children born small for gestational age 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 ft 6 inches in men and 5 ft 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.
 
On July 25, 2003, the FDA approved Humatrope for use in non-GH deficient short stature, defined by the manufacturer as a height standard deviation score (SDS) of -2.25 below the mean. This new indication for GH is the first indication that is based on short stature alone, without an underlying etiology. In May 2008, Genotropin was also approved for this indication.
 
Human growth hormone is usually administered by the member or a family member and is covered under the drug benefit.

Policy/
Coverage:
Effective February 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Recombinant human growth hormone therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following patients:
 
1. Children with documented growth hormone deficiency who are:
1. Below the 5th percentile in height or who are two standard deviations below the mean for sex-adjusted parental height; AND  
2. Growing at a rate that is less than 50th percentile for age; OR
3.Post intracranial surgery or cranial radiation when there has been a documented 6-12 months remission of the disease process
 
Growth hormone deficiency is defined as an abnormal response of less than ten ng/ml to two provocative stimulation tests, such as L-dopa, clonidine, glucagon, propanolol, arginine or insulin.
 
In children who meet the above criteria, growth hormone dosage may be decreased when:
        • Growth velocity is less than 2 cm per year; or
        • Epiphyseal fusion has occurred; or
        • Height reaches the 5th percentile of adult height.
 
An evaluation by an endocrinologist is required.
 
2. Children with height less than the 3rd percentile for chronologic age with chronic renal insufficiency.
        • Growth hormone is discontinued at the time of renal transplant.
 
3.    Patients with AIDS wasting syndrome for 12 weeks only.
        • Clinical information about the patient’s condition and response to growth hormone must be submitted with requests for additional coverage.
4.    Adults with document growth hormone deficiency who meet the following criteria:
1. The patient has been evaluated by an endocrinologist; AND
2. The patient has an abnormal response of less than 10ng/ml to two provocative stimulation tests;     
          AND
3. The dosage of growth hormone is physiologic, not pharmacologic (a maintenance dose rarely exceeds 1.0 mg/day in patients older than 35 years of age).
 
5.     Patients with Turner’s syndrome (45, XO genotype).
        • Therapy is discontinued when the growth velocity is less than 2 cm/year, when epiphyseal fusion has occurred, or when the height reached the 5th percentile of adult height.
 
6.    Patients with 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
 
7.    Patients with short stature due to Noonan syndrome
8.    Promotion of wound healing in patients with 3rd degree burns.
9.    Prevention of growth delay in children with severe burns
10.  Patients with short bowel syndrome receiving specialized nutritional support 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.
    • Optimal management may include dietary adjustments, enteral feedings, parenteral nutrition, fluid, and micronutrient supplements.
    • Zorbitive is administered daily at 0.1 mg/kg subcutaneously up to 8 mg/day. Administration of Zorbitive for longer than 4 weeks has not been adequately studied per the FDA indications.
 11.   Patients with short stature due to SHOX (short stature homeobox-containing gene) deficiency.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Recombinant human growth hormone therapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications or any indication not mentioned above as meeting primary coverage criteria:
 
    • Pediatric patients born small for gestational age who fail to show catch-up growth by age 2 years
    • Children of short stature who do not have documented growth hormone deficiency or Noonan syndrome. Short stature is not considered an illness or an injury and is an exclusion in most member benefit certificates of coverage which states, “the intervention must be a health intervention intended to treat a medical condition. A ‘health intervention’ is an item or service delivered or undertaken primarily to diagnose, detect, treat, palliate or alleviate a medical condition or to maintain or restore functional ability of the mind or body. A ‘medical condition means a disease, illness, injury, pregnancy or a biological or psychological condition.” “Short Stature” is not a medical condition.  
    • For the treatment of chronic catabolic illness (e.g., cancer COPD, etc.), congestive heart failure or glucocorticoid-induced growth deficiency.  
    • For the treatment of geriatric patients or when used as an anabolic therapy to increase body mass or strength.  
    • For the treatment of short stature due to Down’s syndrome.  
    • For the treatment of altered body habitus (e.g., buffalo hump) associated with antiviral therapy in HIV-infected patients.  
    • For the treatment of obesity, cystic fibrosis, idiopathic dilated cardiomyopathy or juvenile idiopathic or juvenile chronic arthritis.  
    • For the treatment of children with “genetic potential” (i.e. lower than expected height percentiles based on parent’s height).
 
For members with contracts without primary coverage criteria, recombinant human growth hormone therapy is considered investigational for the above conditions listed as not meeting primary coverage criteria. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to February 2018
Recombinant human growth hormone therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following patients:
  1. Children with documented growth hormone deficiency who are:
      1. Below the 5th percentile in height or who are two standard deviations below the mean for sex-adjusted parental height; AND
      2. Growing at a rate that is less than 50th percentile for age; or
      3. Post intracranial surgery or cranial radiation when there has been a documented 6-12 months remission of the disease process
 
Growth hormone deficiency is defined as an abnormal response of less than ten ng/ml to two provocative stimulation tests, such as L-dopa, clonidine, glucagon, propanolol, arginine or insulin.
 
In children who meet the above criteria, growth hormone dosage may be decreased when:
    • Growth velocity is less than 2 cm per year; or
    • Epiphyseal fusion has occurred; or
    • Height reaches the 5th percentile of adult height.
 
An evaluation by an endocrinologist is required.
 
2. Children with height less than the 3rd percentile for chronologic age with chronic renal insufficiency.
    • Growth hormone is discontinued at the time of renal transplant.
 
3.    Patients with AIDS wasting syndrome for 12 weeks only.
    • Clinical information about the patient’s condition and response to growth hormone must be submitted with requests for additional coverage.
4.    Adults with document growth hormone deficiency who meet the following criteria:
      1. The patient has been evaluated by an endocrinologist; AND
      2. The patient has an abnormal response of less than 10ng/ml to two provocative stimulation tests; AND
      3. The dosage of growth hormone is physiologic, not pharmacologic (a maintenance dose rarely exceeds 1.0 mg/day in patients older than 35 years of age).
 
5.     Patients with Turner’s syndrome (45, XO genotype).
    • Therapy is discontinued when the growth velocity is less than 2 cm/year, when epiphyseal fusion has occurred, or when the height reached the 5th percentile of adult height.
 
6.    Patients with 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
 
7.    Patients with short stature due to Noonan syndrome
 
8.    Promotion of wound healing in patients with 3rd degree burns.
9.    Prevention of growth delay in children with severe burns
10.  Patients with short bowel syndrome receiving specialized nutritional support 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.
    • Optimal management may include dietary adjustments, enteral feedings, parenteral nutrition, fluid, and micronutrient supplements.
    • Zorbitive is administered daily at 0.1 mg/kg subcutaneously up to 8 mg/day. Administration of Zorbitive for longer than 4 weeks has not been adequately studied per the FDA indications.
 
11.   Patients with short stature due to SHOX (short stature homeobox-containing gene) deficiency.
 
Recombinant human growth hormone therapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications or any indication not mentioned above as meeting primary coverage criteria:
 
  • Children of short stature who do not have documented growth hormone deficiency or Noonan syndrome. Short stature is not considered an illness or an injury and is an exclusion in most member benefit certificates of coverage which states, “the intervention must be a health intervention intended to treat a medical condition. A ‘health intervention’ is an item or service delivered or undertaken primarily to diagnose, detect, treat, palliate or alleviate a medical condition or to maintain or restore functional ability of the mind or body. A ‘medical condition means a disease, illness, injury, pregnancy or a biological or psychological condition.” “Short Stature” is not a medical condition.
  • For the treatment of chronic catabolic illness (e.g., cancer COPD, etc.), congestive heart failure or glucocorticoid-induced growth deficiency.
  • For the treatment of geriatric patients or when used as an anabolic therapy to increase body mass or strength.
  • For the treatment of short stature due to Down’s syndrome.
  • For the treatment of altered body habitus (e.g., buffalo hump) associated with antiviral therapy in HIV-infected patients.
  • For the treatment of obesity, cystic fibrosis, idiopathic dilated cardiomyopathy or juvenile idiopathic or juvenile chronic arthritis.
  • For the treatment of children with “genetic potential” (i.e. lower than expected height percentiles based on parent’s height).
 
For members with contracts without primary coverage criteria, recombinant human growth hormone therapy is considered investigational for the above conditions listed as not meeting primary coverage criteria. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to November 2017
Recombinant human growth hormone therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following patients:
 
  1. Children with documented growth hormone deficiency who are:
      1. Below the 5th percentile in height or who are two standard deviations below the mean for sex-adjusted parental height; AND
      2. Growing at a rate that is less than 50th percentile for age; or
      3. Post intracranial surgery or cranial radiation when there has been a documented 6-12 months remission of the disease process.
 
 Growth hormone deficiency is defined as an abnormal response of less than ten ng/ml to two  provocative stimulation tests, such as L-dopa, clonidine, glucagon, propanolol, arginine or insulin.
 
 In children who meet the above criteria, growth hormone dosage may be decreased when:
      • Growth velocity is less than 2 cm per year; or
      • Epiphyseal fusion has occurred; or
      • Height reaches the 5th percentile of adult height.
 
An evaluation by an endocrinologist is required.
 
2. Children with height less than the 3rd percentile for chronologic age with chronic renal insufficiency.
    • Growth hormone is discontinued at the time of renal transplant.
 
3. Patients with AIDS wasting syndrome for 12 weeks only.
    • Clinical information about the patient’s condition and response to growth hormone must be submitted with requests for additional coverage.
 
4. Adults with document growth hormone deficiency who meet the following criteria:
      1. The patient has been evaluated by an endocrinologist; AND
      2. The patient has an abnormal response of less than 10ng/ml to two provocative stimulation tests; AND
      3. The dosage of growth hormone is physiologic, not pharmacologic (a maintenance dose rarely exceeds 1.0 mg/day in patients older than 35 years of age).
 
5. Patients with Turner’s syndrome (45, XO genotype).
    • Therapy is discontinued when the growth velocity is less than 2 cm/year, when epiphyseal fusion has occurred, or when the height reached the 5th percentile of adult height.
 
6. Patients with growth failure due to Prader-Willi syndrome
 
7. Patients with short stature due to Noonan syndrome
 
8. Promotion of wound healing in patients with 3rd degree burns.
 
9. Prevention of growth delay in children with severe burns
 
10. Patients with short bowel syndrome receiving specialized nutritional support 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.
    • Optimal management may include dietary adjustments, enteral feedings, parenteral nutrition, fluid, and micronutrient supplements.
    • Zorbitive is administered daily at 0.1 mg/kg subcutaneously up to 8 mg/day. Administration of Zorbitive for longer than 4 weeks has not been adequately studied per the FDA indications.
 
11.  Patients with short stature due to SHOX (short stature homeobox-containing gene) deficiency. (Effective April 2013)
 
Recombinant human growth hormone therapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications or any indication not mentioned above as meeting primary coverage criteria:
 
    • Children of short stature who do not have documented growth hormone deficiency or Noonan syndrome. Short stature is not considered an illness or an injury and is an exclusion in most member benefit certificates of coverage which states, “the intervention must be a health intervention intended to treat a medical condition. A ‘health intervention’ is an item or service delivered or undertaken primarily to diagnose, detect, treat, palliate or alleviate a medical condition or to maintain or restore functional ability of the mind or body. A ‘medical condition means a disease, illness, injury, pregnancy or a biological or psychological condition.” “Short Stature” is not a medical condition.
    • For the treatment of chronic catabolic illness (e.g., cancer COPD, etc.), congestive heart failure or glucocorticoid-induced growth deficiency.
    • For the treatment of geriatric patients or when used as an anabolic therapy to increase body mass or strength.
    • For the treatment of short stature due to Down’s syndrome.
    • For the treatment of altered body habitus (e.g., buffalo hump) associated with antiviral therapy in HIV-infected patients.
    • For the treatment of obesity, cystic fibrosis, idiopathic dilated cardiomyopathy or juvenile idiopathic or juvenile chronic arthritis.
    • For the treatment of children with “genetic potential” (i.e. lower than expected height percentiles based on parent’s height).
 
For members with contracts without primary coverage criteria, recombinant human growth hormone therapy is considered investigational for the above conditions listed as not meeting primary coverage criteria.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to October 2011
Human Growth Hormone meets primary coverage criteria for effectiveness and is covered to increase adult height for children who have documented growth hormone deficiency who are:
    • Below the fifth percentile in height or who are two standard deviations below the mean for sex-adjusted parental height;
    • Growing at a rate that is less than fiftieth percentile for age; or
    • Post intracranial surgery or cranial radiation when there has been a documented 6-12 months remission of the disease process.
Growth hormone deficiency is defined as an abnormal response of less than ten ng/ml to two provocative stimulation tests, such as L-dopa, clonidine, glucagon, propranolol, arginine or insulin.
 
In children who meet the above criteria growth hormone dosage may be decreased when:
    • Growth velocity is less than 2 cm per year;
    • Epiphyseal fusion has occurred; or
    • Height reaches the 5th percentile of adult height.
An evaluation by an endocrinologist is required.
 
Human growth hormone is not covered for children of short stature who do not have documented  growth hormone deficiency.  Short stature is not considered an illness or an injury and is an exclusion in the member certificate of coverage.
 
Human Growth Hormone is covered for adults with growth hormone deficiency who have been evaluated by an endocrinologist and have an abnormal response of less than 10 ng/ml to two provocative stimulation tests.  The dosage of growth hormone is physiologic, not pharmacologic.  A maintenance dose rarely exceeds 1.0 mg/day in patients older than 35 years of age.  
 
Human Growth Hormone is covered for children with chronic renal failure who have height less than the 3rd percentile.  Growth Hormone therapy is discontinued at the time of renal transplant.
 
Human Growth Hormone is covered for patients with Turner's Syndrome  (45, XO genotype).  Therapy is discontinued when the growth velocity is less than 2 cm/year, when epiphyseal fusion has occurred, or when the height reached the 5th percentile of adult height.
 
Human Growth Hormone is covered for HIV wasting syndrome for 12 weeks only.  Clinical information about the patient's condition and response to growth hormone must be submitted with requests for additional coverage.
 
Human growth hormone for the treatment of chronic catabolic illness (e.g., cancer, COPD, etc), congestive heart failure or for glucocorticoid-induced growth deficiency is not covered based on benefit certificate primary coverage criteria because improvement in net health outcomes in these situations has not been documented in medical literature.
 
For members with contracts without primary coverage criteria,  human growth hormone for the treatment of chronic catabolic illness (e.g., cancer, COPD, etc), congestive heart failure or for glucocorticoid-induced growth deficiency is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.
 
Human growth hormone for geriatric members or when used as an anabolic therapy to increase body mass or strength is not covered as it is not treatment for an injury or illness.  Treatment not related to injury or illness is an exclusion in the member certificate of coverage.
 
Non-coverage of short stature is based on the benefit certificate language which states, "the intervention must be a health intervention intended to treat a medical condition.  A "health intervention" is an item or service delivered or undertaken primarily to diagnose, detect, treat, palliate or alleviate a medical condition or to maintain or restore functional ability of the mind or body.  A "medical condition" means a disease, illness, injury, pregnancy or a biological or psychological condition."  "Short Stature" is not a medical condition.

Rationale:
The following discussion focuses on the most controversial aspects of Growth Hormone (GH) use.
 
GH Use in Short-Statured Children Without Documented GH Deficiency
While GH therapy in patients with classic GH deficiency is accepted, the use of GH in short- statured patients without GH deficiency, as identified by standard provocation tests, is controversial. The controversy is related to difficulties in laboratory diagnosis of GH deficiency; the lack of pretreatment factors, either laboratory or auxological (i.e., various measurements of height), which can predict response to GH; the lack of long-term outcome data to show whether initial gains in growth velocity will result in increased adult height; and lack of data to determine if such an increase in height is associated with any beneficial functional or psychosocial outcome. Surveys of endocrinologists suggest that laboratory measures of GH secretion are of limited usefulness in the decision of whether to initiate therapy.  The most useful criteria cited by endocrinologists appear to be abnormal height, growth velocity, and delayed bone age. However, there are inadequate outcome data in terms of final height to validate this approach. These surveys also suggest that GH treatment is sought primarily to treat the potential psychosocial morbidity of short stature, and yet this outcome has not been studied in GH recipients. In addition, other studies have suggested that short stature is only variably related to psychosocial morbidity.  There has been 1 controlled trial that examined the behavior of children without documented GH deficiency who were treated with GH due to idiopathic short stature.  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 there have been no demonstrated psychosocial benefits of GH therapy, likewise, there have been no documented psychosocial ill effects of GH treatment.
 
In January 1997, the American Academy of Pediatricians (AAP) published a document that recommended the following patient selection criterion for children with short stature not associated with classic GH deficiency:  “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.”
 
In addition, the AAP noted:
“Numerous considerations argue against widespread administration of GH therapy to other short children. First, the therapy’s risk benefit ratio in this population is not established. There could be unknown long-term risks, and the treatment could result in either no increase or only an insignificant increase in final adult height. . . . Even if the clinical data show a positive risk benefit ratio, however, the benefits of GH therapy will inevitably remain somewhat elusive. Individual children may escape the stigma of being very short, but a group of very short children will always exist. On a broader scale, the best “therapy” for these children would be a campaign against the current prejudice against short people instead of an implicit medical reinforcement of such prejudice.”
 
GH Use in Small for Gestational Age Children
As noted in the Description section, in 2001, one GH preparation received FDA approval for treatment of small for gestational age children. This FDA approval was based on 4 randomized, open-label controlled clinical trials.  Patients were observed for 12 months before being randomized to receive either 0.24 mg/kg/week or 0.48 mg/kg/week GH or no treatment for 24 months. After 24 months all patients received GH. In patients receiving the higher dosage of 0.48 mg/kg/wk, the patients' height improved from a baseline of -3.4 standard deviations to -1.7 standard deviations below the mean. In contrast, in the control group the standard deviation score improved to a lesser degree, from -3.1 to -2.9 standard deviations below the mean. The issues associated with this indication for GH are similar to those for other short-statured children without documented GH deficiency. There are no documented functional impairments associated with short stature and no data regarding final adult height in the control or treatment group. It should be noted that the dosage recommended for small for gestational age children, 0.48 mg/kg/week, is a supra physiologic dose. For example, in patients with documented GH deficiency, in which the intent is to provide normal physiologic replacement levels of GH, the recommended dosage is only 0.24 mg/kg/week. 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 above, there are inadequate data to document that short-statured youths have either low self-esteem or a higher than average amount of behavioral or emotional problems.
 
Turner Syndrome
Short stature is almost universal in Turner's 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 ft 10 inches). Unlike Prader-Willi syndrome, GH deficiency is not seen. The FDA approvals for Humatrope and Nutropin were based on the results of randomized, controlled clinical trials that included final adult height as the outcome. A group of patients with Turner's syndrome given Humatrope at a dosage of 0.3 mg/kg/week for a median of 4.7 years achieved a final height of 146.0 +/6.2 cm (57.5 +/-2.25 inches) compared to an untreated control group who achieved a final height of 142.1 +/- 4.8 cm (56 +/- 2 inches).  The results with Nutropin were similar.  While the data regarding Turner's syndrome are somewhat unique in that final height is known, the clinical significance of a mean increase in height of 3.9 cm (1.75 inches) is unknown.
 
GH Therapy in Older Adults without Documented Growth Hormone Deficiency
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 GH deficiency. Older individuals experience changes in body composition, loss of muscle mass, and decreases in bone mineral density that are similar to changes seen in adults with biochemically verified GH deficiency. Based on these observations, GH therapy has been investigated in older adult without organic pituitary disease. This policy references a 2001 Blue Cross Blue Shield Association Technology Evaluation Center assessment regarding this off label application, which offered the following observations and conclusions:
    • In 1998 the American Association of Clinical Endocrinologists (AACE) published clinical guidelines regarding GH use. Regarding the use of GH in adults, the AACE guidelines noted that “the benefits of GH supplementation in aging patients remain to be established.” In 1997, the Growth Hormone Research Society published consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency. These guidelines state, “partial GH deficiency exists, but further research is needed to distinguish it from physiological causes of reduced GH secretion, e.g., aging. Furthermore, the benefits of treatment of partial GH deficiency remain to be established.”
    • Only 6 small controlled trials with at least 10 patients per treatment arm have examined the effect of GH therapy on older patients who may have partial GH deficiency, as compared to younger populations. These trials used much higher doses than are currently recommended and suffered from potential bias due to disproportionate numbers of dropouts from adverse events. Bone mineral density outcomes were most often reported, but results did not show consistent time frame within the time frame tested and have not been related to fracture rates. Trials tended to report increases in lean body mass and decreases in fat mass in treated patients compared to controls, but not all improvements are statistically significant; different methods of measuring body composition across trials may be affected by GH-induced changes in extracellular fluid, and may not be comparable.
    • It is not possible to prove effectiveness of GH treatment or lack thereof unless other wise 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. Limited results do not suggest marked improvement with GH therapy and, in general, are insufficient to permit conclusions regarding the effectiveness of GH at improving disability and quality of life in older populations.
 
GH Therapy as a Treatment of 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 dorso cervical fat pad ("buffalo hump").  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 and colleagues who treated 10 HIV-infected patients with fat redistribution syndrome with GH for 3 months.  The authors reported improved waist/hip ratio and mid-thigh circumference.
 
A systematic review of growth hormone found that literature published on randomized, controlled trials evaluating GH therapy in the healthy elderly is limited but suggests that it is associated with small changes in body composition and increased rates of adverse events.  On the basis of this evidence, GH cannot be recommended as an antiaging therapy.
 
2011 Update
This policy is being updated with a literature review through September 2011.  
 
The largest study published to date on safety of GH treatment includes data on 54,996 included in a postmarketing surveillance registry established by Genentech, Inc. (Bell, 2010). The study was initiated due to concerns about long-term safety of GH, in particular, cases of de novo leukemia in patients without risk factors. The most common indications for GH use among children in the database were idiopathic GH deficiency (42.5%), idiopathic short stature (17.8%), organic GH deficiency (15.2%) and Turner syndrome (9.3%). As of January 1, 2006, a total of 4,084 adverse events (6.2%), including 1559 (2.4%) serious adverse events 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). The results of this study provide some evidence that the rate of malignancies was not increased in patients treated with GH. However, the registry study lacked a concurrent comparison with untreated patients to compare actual rates of malignancy and other adverse events.
 
In 2010, the National Institute of Health and Clinical Excellence (NICE) in the U.K. issued guidance on human growth hormone for growth failure in children. (41) 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 (AACE) issued updated guidelines on growth hormone use in growth hormone-deficient adults and transition patients (Cook, 2009).  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.
 
Growth hormone has been proposed as an off-label indication for the treatment of cystic fibrosis. Since use of HGH is not a FDA approved for this indication, this use does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. A systematic review identified 10 controlled trials evaluating GH for treating patients with cystic fibrosis (Phung, 2010). One study was placebo-controlled, 8 compared GH therapy to no treatment and the remaining trial compared GH alone to glutamine or glutamine plus GH. In one 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 could be pooled, however, on frequency of hospitalizations although the authors did not report the number of studies included in their meta-analyses. In trials with a duration 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). The authors commented that GH is a promising therapy for treatment of cystic fibrosis but there a number of important research questions that must be answered about; in particular, there is a need for high-quality studies on health outcomes.
 
The coverage statement is updated to include additional FDA approved indications.
 
2012 Update
A search of the MEDLINE database through September 2012 identified no published literature that would prompt a change in the coverage statement.
 
According to the drug prescribing information, GH therapy use has been associated with sudden death in children with Prader-Willi syndrome. 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.
 
In 2012, Sode-Carlsen and colleagues in Scandinavia evaluated GH therapy for adults with genetically verified Prader-Willi syndrome.   In the RCT, 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 compared to baseline), and fat mass decreased by a mean of 4.2 kg (p<0.001 compared to 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 (HDL)-cholesterol or triglycerides, peak expiratory flow, fasting glucose, fasting insulin and physical function. During the 12-month treatment period, the level of low-density lipoprotein (LDL)-cholesterol decreased significantly more in the GH-treated compared to control group (mean difference of 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 children with Prader-Willi Syndrome and growth failure, GH deficiency is assumed, and GH replacement may be considered medically necessary without documentation of GH deficiency.  Genotropin and Omnitrope are contraindicated in Prader-Willi syndrome patients who are severely obese or who have severe respiratory impairment.
 
 
In 2012, Hodson and colleagues published a Cochrane review of RCTs evaluating GH treatment in children with chronic kidney disease.  A total of 7 RCTs with 809 children met the review criteria:
    • Had to include children 18 years-old or younger who were diagnosed with chronic kidney disease and were pre-dialysis, on dialysis, or post-transplant
    • Needed to compare GH treatment with placebo, no treatment or a different GH regimen and needed to include height outcomes.   
 
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/week) compared with placebo or no specific therapy resulted in a statistically significant increase in height standard deviation score at 1 year (8 studies, mean difference [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 to control (MD: 3.88 cm/year, 95% CI: 3.32 to 4.44).
 
There are multiple on-going clinical trials listed on the clinicaltrials.gov site.
 
2013 Update
Children with Short Stature Due to SHOX (short stature homeobox-containing gene) Deficiency
 
Treatment of children with short stature due to SHOX deficiency is an FDA-approved indication for GH therapy (Humatrope). A 2010 Health Technology Assessment on GH treatment of growth disorders in children conducted a systematic review and identified one RCT evaluating GH therapy for children with short stature due to SHOX (Takeda, 2010). This industry-sponsored open-label multicenter study was published by Blum and colleagues in 2007 (Blum, 2007).  It included 52 pre-pubertal 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/year) 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 events were reported for either of the two above groups of patients.
 
A statement has been added to the coverage section for coverage of growth hormone therapy for the treatment of short stature due to SHOX deficiency.
 
2014 Update
A literature search conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Growth Hormone Deficiency in Adults
 
In adults with GH deficiency, there is evidence from randomized controlled trials (RCTs) that treatment leads to increases in lean body mass and decreases in body fat (Beauregard, 2008). 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 (Widdowson, 2008; Widdowson, 2010). There is also evidence from a meta-analysis of 20 RCTs that GH therapy is associated with increased bone mineral density in adults with GH deficiency (Xue, 2013). 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 (Hoffman, 2004; Maison, 2003; Sesmilo, 2000; Gotherstrom, 2001).
 
Growth Failure Due to Prader-Willi Syndrome
 
Several studies have shown patient improvements with use of GH. For example, a 2008 RCT reported by Festen and colleagues involving 42 infants and 49 prepubertal children (age 3 to 14 years), found that GH treatment significantly improved height, body mass index (BMI), head circumference, and body composition (Feston, 2008). In 2012, the investigators published cognitive outcomes in children participating in this trial (Siemensma, 2012). 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.
 
GH Use in Children with Short Stature Associated with Chronic Renal Insufficiency
 
In 2013, Wu and colleagues 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 (Wu, 2013). Five trials with a total of 401 participants met the review’s 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 growth hormone compared to a no treatment control group. At the beginning of the year, both groups had a negative height standard deviation score (SDS), with no statistically significant differences between groups. After one 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.
 
GH Therapy for Severe Burns
 
A Cochrane systematic review, published in 2012, included RCTs evaluating the impact GH therapy on the healing rate of burn wounds (Breederveld, 2012). Thirteen trials were identified that compared GH therapy to 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 to placebo (mean difference [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 to 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 to controls (RR: 2.65, 95% CI: 1.68-4.16).
 
GH Therapy for Cystic Fibrosis
 
A 2013 Cochrane systematic review evaluated GH therapy for improving lung function, nutritional status and quality of life in children and young adults with cystic fibrosis (Thaker, 2013). 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 cystic fibrosis (Phung, 2010). One study was placebo-controlled, 8 compared GH therapy to no treatment and the remaining trial compared GH alone to glutamine or glutamine plus GH. In one 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).
 
In 2013, a Growth Hormone Research Society workshop issued consensus guidelines on recombinant GH (rhGH) therapy in Prader-Willi syndrome (PWS) (Deal, 2013). The following were among the group’s recommendations:
  • “After genetic confirmation of the diagnosis of PWS, 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 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 (Cohen, 2008). 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.
 
Clinical Trial identified:
 
Severe Decrease of Growth Velocity in Children With Anorexia Nervosa. Therapeutic Trial of Growth Hormone (OREX) (NCT01626833) (Hôpitaux de Paris, 2013): 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.
 
2014 Update
A literature search conducted through September 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
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 (Patterson, 2014). 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.
 
In 2014, Poidvin et al reported on the same data, focusing on risk of stroke in adulthood among childhood users of GH therapy (Poidvin, 2014). 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 to general population controls. Standard incidence ratios (SIR) 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 of 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 above analyses from this research team, there were a small number of events (ie deaths or stroke),and thus conclusions from these data are not definitive on the long-term safety of GH therapy.
 
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 bone mineral density (BMD) (Barake, 2014).  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 1-5% 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.
 
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 (Rues, 2013). This was a 2-year single-blind trial that included 22 children newly diagnosed with Prader-Willi syndromen (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 (AIMS).
 
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 to placebo, compared to no treatment and compared to controls of normal height. Idiopathic short stature is defined as more than 2 SDs 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.
 
2015 Update
A literature search was conducted using the MEDLINE database through September 2015. There was no new literature identified that would prompt a change in the coverage statement.  The key publications identified are summarized below.
 
Short Stature Due to Noonan Syndrome
In 2015, Giacomozzi et al published a systematic review of literature on the effect of GH therapy on adult height (Giacomozzi, 2015). Included in the review were studies treating individuals with a diagnosis of Noonan syndrome with no other causes of short stature and a normal karyotype in females. In addition, studies needed to follow patients for at least 3 years. A total of 23 studies met the inclusion criteria; none were RCTs and only 1 was controlled. Three of the studies were case reports and the remainder were prospective or retrospective cohort studies. In the 1 controlled study (MacFarlane et al, 2001), over the 3 year followup, the GH treated group gained a mean of 3.3 cm more than the untreated group. Among the uncontrolled studies, 2 reported adult height. Mean height SDS was -2.8 (SD: 0.6) and mean adult height SDS was -1.4 (SD: 0.9). Two uncontrolled studies reported near-adult height which was -2.1 (SD: 0.9). In addition, 2 studies reported a change in height SDS corresponding to 8.6 cm (SD: 5.9). The data are limited by the paucity of controlled studies and lack of RCTs.
 
Treatment of HIV Wasting
In 2004, Moyle et al published a systematic review of controlled and uncontrolled studies on selected treatments of HIV wasting (Moyle, 2004). To be included, studies needed to include more than 10 patients and have a treatment duration of at least 2 weeks. Studies of GH therapy showed significant increases in lean body mass compared to placebo. Two of the studies evaluating GH treatment found statistically significant improvements in some aspects of quality of life after 12 weeks.
 
Practice Guidelines and Position Statements
In 2015, the Pediatric Endocrine Society Drug and Therapeutics Committee published an evidence-based report on risk of neoplasia in patients receiving GH therapy (Raman, 2015). The reported 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, cases 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.   
 
2016 Update
A literature search conducted through September 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
SHORT STATURE DUE TO PRADER-WILLI SYNDROME
Lo and colleagues conducted a 2 year RCT of GH therapy versus no treatment and then followed children on GH therapy for an additional 6 years (Lo, 2015). The study 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 in the GH treated and no treatment groups. Findings were similar at the end of the 8-year follow-up period.
 
TREATMENT OF AIDS WASTING
A 2005 double-blind RCT by Evans and colleagues included 700 patients with HIV-associated wasting (Evans, 2005).  Patients assigned to human growth hormone had significantly greater increase in exercise capacity, the primary outcomes, than patients assigned to placebo.
 
In November 2015, results from the Growth Hormone Safety Workshop were published by Allen and colleagues in the European Journal of Endocrinology (Allen, 2016). The Workshop was convened by the Growth Hormone Research Society, the European Society of Paediatric Endocrinology, and the Pediatric Endocrine Society. The purpose was to reappraise the safety of rhGH. The position statement concluded:
 
  • After following children and adults for tens of thousands of person-years, the safety profile of rGH remains good when rhGH is used for approved indications and at recommended doses. There is no evidence supporting an association between rhGH and overall mortality, risk of new primary cancer, risk of recurrence of primary cancer, risk of stroke, or risk of cardiovascular disease.
  • A carefully-designed cohort study, providing continued long term surveillance of patients treated with rhGH, would address the current limitations of safety data (for example, inconsistent definitions of outcomes, low incidence outcomes, and lack of dose-specific assessments).
 
2017 Update
A literature search conducted through August 2017 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
Swerdlow and colleagues published results from the Safety and Appropriateness of Growth Hormone Treatments in Europe (SAGhE) study, which compared the risk of cancer mortality and cancer incidence among patients receiving GH therapy with national population rates (Swerdlow, 2017).  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 GH deficiency, idiopathic short stature, and prenatal growth failure. Other common diagnoses leading to GH treatment included: Turner syndrome, pituitary hormone deficiency, and CNS 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 followup 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.
 
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.
 
There have been numerous case reports of sudden unexpected death in Prader-Willi syndrome patients undergoing GH therapy (Van Viet, 2004; Grugni, 2005).  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 (Pfizer, 2014; Lilly, 2016).
 
Kuppens and colleagues 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 (Kuppens, 2016). 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.
 
SHORT STATURE DUE TO CHRONIC RENAL INSUFFICIENCY
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 and colleagues compared the final height of children treated (n=68) and not treated (n=92) with GH who had chronic kidney disease (Bizzarri, 2017). Mean follow-up was 9 years. Among cases, 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 not significant decrease in height SDS among non-GH-treated children. However, final height SDS did not differ significantly between treated and non-treated children (p=0.3). The reason for no difference in final height may be that the non-treated children had a significantly higher height SDS at baseline compared with the treatment group. This difference may represent the reason GH treatment was not initiated in the control group.
 
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 and colleagues compared the craniofacial morphology of 13 patients with Turner syndrome who had been treated with GH to 13 patients with Turner syndrome who had not been treated with GH (Juloski, 2016). 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.
 
SHORT STATURE DUE TO SHORT STATURE HOMEOBOX-CONTAINING GENE DEFICIENCY
Benabbad and colleagues published long-term height results and safety data from patients in the RCT by Blum et al and from a subset of patients with short stature, due to SHOX deficiency from the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) (Benabbad, 2017). 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/year, 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 initiation was 11.0 years, mean age at near-adult height was 15.7 years, and GH 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 (TEAE) reported in the GeNeSIS patients were: precocious puberty (2.6%) and arthralgia (2.4%). The most common TEAEs reported in the RCT patients were: headache (18.4%) and congenital bowing of long bones (18.4%).
 
ALTERED BODY HABITUS RELATED TO ANTIRETROVIRAL THERAPY FOR HIV INFECTION
Lindboe and colleagues 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 because high-dose GH has been associated with adverse events relating to inflammation (Lindboe, 2016). Participants were randomized to GH 0.7 mg/day (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), as high levels of CRP and suPAR indicate inflammation. After 40 weeks, low-dose GH significantly lowered Creactive protein. Low-dose GH lowered suPAR as well, but the difference was not significant, even after controlling for age, weight, smoking status, and lipodystrophy.
 
TREATMENT OF PRECOCIOUS PUBERTY IN CONJUNCTION WITH GNRH THERAPY
Liu and colleagues published a meta-analysis comparing GnRH with the combination therapy of GH with GnRH for the treatment of females with idiopathic central precocious puberty (Liu, 2016). 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. MINORS scores 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 (mean difference in centimeters, 2.8 [95% CI, 1.8 to 3.9], 3.9 [95% CI, 3.1 to 4.7], and 3.5 [95% CI, 1.0 to 6.0], respectively). When treatment duration was less than 1 year, no significant differences in the height outcomes were found.
 
 
2018 Update
 
Growth Hormone (GH) Use in Small for Gestational Age (SGA) Children
Schepper et al randomized children aged 19-29 who had been diagnosed as SGA at birth to receive GH or no treatment.  After 24 months, the treated children had a significant increase in height, but no significant difference in mental or psychomotor development relative to the controls.
 
Schwartz et al evaluated the safety of GH for SGA children, evaluating development of diabetes, efficacy, adverse events, malignancies, and development of anti-rhGH antibodies during treatment.  249 children completed 2 years of treatment, with no child developing a fasting glucose or 2-hour oral glucose tolerance test exceeding >126 or >200 mg/dL.  There were no adverse alterations in body mass.  76.2% of the children experienced significant adverse events, but most were thought unrelated to the GH.  
 
Horikawa et al administered GH for 260 weeks to 80 Japanese children with short stature who were SGA. LDL cholesterol, total cholesterol (TC), insulin levels were measured.  LDL and TC levels decreased over the course of treatment, but insulin resistance developed over time.  
 
Based on these trial results, policy has been revised to include statement of non-coverage for the use of growth hormone for the indication of SGA.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
GHD in Adults
Ishii et al  published an industry-funded, multicenter, observational study of GH therapy for adults with GHD (Ishii, 2017). One hundred sixty-one patients were eligible for quality of life analysis using the Adult Hypopituitarism Questionnaire (AHQ). For male and female patients combined, AHQ scores were improved from baseline in both psycho-social and physical domains. Women had significantly lower AHQ scores than men throughout, however, the net changes in AHQ scores did not differ significantly between men and women (psycho-social domain: 4.90 vs 4.36; p=0.833; physical domain: 5.04 vs 2.29; p=0.213; respectively), despite an increase in GH dose such that insulin-like growth factor-1 levels for women reached that of men. The study was limited due to loss to follow-up, data collection being on patient recall, the observational design, and lack of a control group.
Short Stature Due to Turner Syndrome
 
Li et al conducted a meta-analysis to determine the effect of recombinant human GH treatment on height outcomes in patients with Turner syndrome (Li, 2018). Eleven RCTs (total N=1122 patients), published between 1986 and 2011, were identified for the analysis. Compared with controls, there was a significant increase in final height (mean difference [MD], 7.2 cm; 95% CI, 5.27 to 9.18 cm; p<0.001), height SD (standardized mean difference [SMD], 1.22 cm; 95% CI, 0.88 to 1.56 cm; p<0.001), and height velocity (MD=2.68 cm/y; 95% CI, 2.34 to 3.02 cm/y; p<0.001) for patients receiving GH. After 1 year, bone age increased slightly for the GH group (SMD=0.32/y; 95% CI, 0.1 to 0.54/y; p=0.004). The meta-analysis was limited by the small number of available studies and the lack of sufficient data on final height.

CPT/HCPCS:
96372Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
J2170Injection, mecasermin, 1 mg
J2940Injection, somatrem, 1 mg
J2941Injection, somatropin, 1 mg
J3490Unclassified drugs

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