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MP 5.01.06 Human Growth Hormone

Medical Policy    
Section
Prescription Drugs 
Original Policy Date
11/1/97
Last Review Status/Date
Reviewed with literature search/9:2013
Issue
9:2013
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Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Description

Recombinant human growth hormone (GH) is U.S. Food and Drug Administration (FDA)-approved for a variety of indications and is also proposed for various non-labeled indications such as cystic fibrosis and treatment of older adults without documented GH deficiency.

Background

Human growth hormone (GH), also known as somatotropin, is synthesized in somatotropic cells of the anterior lobe of the pituitary gland. Growth hormone deficiency can occur due to a variety of conditions, such as:

  • Pituitary tumor
  • Pituitary dysfunction due to prior surgery or radiation treatment
  • Extrapituitary tumor
  • Sarcoidoisis, and/or other infiltrating disorders
  • Idiopathic

Growth hormone deficiency in children is manifested primarily by short stature. In adults, as well as in some children, other abnormalities associated with growth hormone deficiency are often evident. These include changes in body composition, higher levels of low-density lipoprotein (LDL) cholesterol, lower bone density, and a decreased self-reported quality of life compared to healthy peers. Some evidence also suggests that there may be increases in cardiovascular disease and overall mortality, but it is less clear whether growth hormone deficiency is causative for these outcomes.

Beginning in 1985, recombinant GH has been marketed for a variety of U.S. Food and Drug Administration (FDA)-labeled indications as follows:

 

Genotropin (Pfizer)

Humatrope (Lilly)

Norditropin (Novo-Nordisk)

Nutropin (Genen-tech)

Saizen (Serono)

Serostim (Serono)

Tev-Tropin (Ferring)

Zorbtive (Serono)

Omnitrope (Sandoz)

Growth failure, peds pts with inadequate endogenous GH

yes

yes

yes

yes

yes

 

yes

 

yes

Growth failure due to Prader-Willi syndrome

yes

             

yes

Replacement therapy in adults with GH deficiency

yes

yes

yes

yes

yes

     

yes

Growth failure associated with chronic renal insufficiency

     

yes

         

HIV wasting or cachexia

         

yes

     

Children born small for gestational age, who fail to show catch-up growth by age 2 years

yes

yes

yes

         

yes

Short stature (height *SDS <-2.25) in non-GH-deficient peds pts

yes

yes

 

yes

         

Short stature due to Turner's syndrome (45, XO)

yes

yes

yes

yes

       

yes

Treatment of short bowel syndrome

             

yes

 

Short stature in peds pts with SHOX (short stature homeobox-containing gene) deficiency

 

yes

             

Short stature in peds pts with Noonan syndrome

   

yes

         

yes

SDS; standard deviation score; HIV, human immunodeficiency virus

A major point of controversy is what defines “inadequate secretion of normal endogenous growth hormone,” and what constitutes “growth failure.” Prior to the availability of biosynthetic GH, GH was rationed to children with classic GH deficiency (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 GH deficiency, neurosecretory GH dysfunction, constitutional delay in growth and development (CDGD), or idiopathic short stature. “Classic” GH deficiency is suggested when the abnormal growth velocity (typically below the 10th percentile) or height is more than 2 standard deviations (SD score) below the current population mean, 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 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.

In 2001, Genotropin received an 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 feet, 6 inches in men and 5 feet, 1 inch in women. GH has been investigated in these children, based in part on the hypothesis that a GH resistance is a possible etiology of the growth retardation. In 2003, the FDA approved a recombinant human growth hormone product 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 indication for GH was the first indication that is based on short stature alone, without an underlying etiology.


Policy

 

Recombinant human growth hormone (GH) therapy may be considered medically necessary for the following patients (see specific patient selection criteria in Policy Guidelines):

  1. Children with proven GH deficiency
  2. Children with height less than the 3rd percentile for chronologic age with chronic renal insufficiency
  3. Patients with AIDS [acquired immunodeficiency syndrome] wasting
  4. Adults with proven GH deficiency
  5. Patients with Turner’s syndrome
  6. Children with growth failure due to Prader-Willi syndrome
  7. Patients with short stature due to Noonan syndrome
  8. Promotion of wound healing in burn patients
  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
  11. Children with short stature due to SHOX (short stature homeobox-containing gene) deficiency

The following FDA-approved indications are considered not medically necessary:

  1. Pediatric patients born small for gestational age (SGA) who fail to show catch-up growth by age 2 years
  2. Children with height standard deviation score of -2.25 or below without documented GH deficiency

Recombinant human growth hormone is considered investigational for all other applications including, but not limited to the following:

  • Constitutional delay (lower than expected height 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) analogs as a treatment of precocious puberty
  • GH therapy in older adults without proven deficiency
  • 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
  • Treatment of altered body habitus (e.g., buffalo hump) associated with antiviral therapy in HIV- infected patients
  • Treatment of obesity
  • Treatment of cystic fibrosis
  • Treatment of idiopathic dilated cardiomyopathy
  • Treatment of juvenile idiopathic or juvenile chronic arthritis
  • Treatment of children with “genetic potential” (i.e., lower than expected height percentiles based on parents’ height)


Policy Guidelines

The numbered guidelines correspond to the indications listed in the Policy section above.

Medically Necessary Indications:

1. Both children and adults (see No 4, below) with proven GH deficiency are considered appropriate candidates for GH therapy.

For adults, proven GH deficiency is defined as:

  1. An abnormal response to TWO provocative stimulation tests, such as L-dopa, clonidine, glucagons, arginine, GH-releasing hormone (GHRH), or insulin. The insulin tolerance test is considered the best predictor of GH deficiency; however, this test is contraindicated in patients with seizures or coronary artery disease. A provocation test using arginine and GHRH is also acceptable and is considered more stringent than tests using arginine alone or levodopa alone. 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 recombinant human GH reference preparations. Twenty-four hour continuous measurements of GH, serum levels of IGF-I, or serum of levels IGFBP [insulin-like growth factor-binding protein] are considered inadequate to document GH deficiency.
  2. An abnormal response to ONE provocative stimulation test in patients with defined central nervous system pathology, history of irradiation, multiple pituitary hormone deficiency, or a genetic defect.
  3. Low IGF-I concentration in patients with complete hypopituitarism.

For children, no criteria have been established for the laboratory diagnosis of GH deficiency, and criteria may vary regionally. The recommended dosage for children with GH deficiency is 0.3 mg/kg per week, divided into daily or 6 times per week injections. In children, GH therapy is typically discontinued 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.

2. Chronic renal insufficiency is defined as a serum creatinine of greater than 1.5 mg/dL (or 1.4 for women and 1.7 for men) or a creatinine clearance <75 mL/min per 1.73 m2. In 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.

3. AIDS (acquired immunodeficiency syndrome) wasting is defined as a greater than 10% of baseline weight loss that cannot be explained by a concurrent illness other than HIV (human immunodeficiency virus) infection. Patients treated with GH must simultaneously be treated with antiviral agents. Therapy is continued until this definition is no longer met.

4. Adults with GH deficiency are defined as in No. 1 above. Only about 25% of those children with documented GH deficiency will be found to have GH deficiency as adults. Therefore, once adult height has been achieved, subjects should be retested for GH deficiency to determine if continuing replacement therapy is necessary. These transition patients who require further treatment are usually started at doses of 0.4 to 0.8 mg/day, and titered to maintenance doses of 1.2 to 2.0 mg/day. Adults with GH deficiency not related to idiopathic deficiency of childhood (e.g., pituitary tumor, pituitary surgical damage, irradiation, trauma) are usually started at 0.1 to 0.3 mg/day; the dose is titered to clinically desired end points (improved body composition, quality of life, reduction in cardiovascular risk factors), usually resulting in maintenance doses of 0.2 to 0.5 mg/day for men and 0.4 to 1.0 mg/day for women. The FDA cautions that the safety and effectiveness of GH therapy in adults aged 65 and older has not been evaluated in clinical studies. Therefore, it is noted that elderly patients may be more sensitive to the action of GH therapy and may be more prone to develop adverse reactions.

5. Turner’s syndrome is defined as a 45, XO genotype.

6. Prader-Willi syndrome is a genetic disorder characterized by a microdeletion in the long arm of chromosome 15. Clinically, the syndrome presents as a complex multisystem disorder characterized by excessive appetite, obesity, short stature, characteristic appearance, developmental disability, and significant behavioral dysfunction. GH deficiency has been demonstrated in most tested patients with Prader-Willi syndrome.

Sleep studies are recommended prior to initiation of growth hormone therapy for obese pediatric patients with Prader-Willi syndrome.

7. GH therapy for burn patients should be limited to those patients with third-degree burns.

8. Children with severe burns have been successfully treated with 0.05 to 0.2 mg/kg recombinant GH (rhGH) per day during acute hospitalization and for up to 1 year after burn.

9. Growth hormone for patients with short bowel syndrome should be limited to patients 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. Zorbtive is administered daily at 0.1mg/kg subcutaneously up to 8 mg/day. Administration of Zorbtive for longer than 4 weeks has not been adequately studied per the FDA indications.

Not Medically Necessary Indications:

1. Pediatric patients born small for gestational age. There are no established criteria for small for gestational age or “catch-up” growth. However, in the data submitted to the FDA as part of the approval process, the mean height of enrolled patients was at least 2 standard deviations below the mean. Absence of catch-up growth was defined as a height velocity below 1 standard deviation score, adjusted for age.

2. Pediatric patients with short stature. "Short stature" has been defined by the American Association of Clinical Endocrinologists and the Growth Hormone Research Society as height more than 2 standard deviations (SD) below the mean for age and sex. The FDA-approved indication is for children with a height standard deviation score (SDS) of -2.25 below the mean. Using this proposed definition, approximately 1.2% of all children would be defined as having idiopathic short stature and considered potentially treatable under these indications. Note that this indication is considered not medically necessary.


Benefit Application
BlueCard/National Account Issues

Human growth hormone may be adjudicated under the Drug Benefit as an injectable.

State or federal mandates may require coverage eligibility for drugs used according to their FDA-labeled indications. In this policy, two FDA-labeled indications are considered “not medically necessary,” i.e., pediatric patients born small for gestational age, and pediatric patients with short stature.


Rationale

The policy was created in 1997 and was updated regularly with searches of the MEDLINE database. The most recent update covers the period of July 2012 through July 11, 2013.

Outcome Measures in Growth Hormone Research

The most common outcome measure reported in growth hormone research is change in height. For some situations, such as in patients with documented growth hormone deficiency 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 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 adverse effects 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 growth hormone (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 growth hormone deficiency (GHD) (42.5%), idiopathic short stature (17.8%), organic GH deficiency (15.2%), and Turner’s syndrome (9.3%). As of January 1, 2006, a total of 4,084 adverse events (6.2%), including 1,559 (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). This study lacked a concurrent comparison with untreated patients to compare actual rates of malignancy and other adverse events.

A 2012 analysis of long-term mortality after GH treatment was conducted by Carel and colleagues using French registry and vital statistics data. (4) A total of 6,928 children who initiated GH treatment between 1985 and 1996 were included in the study. Indications for GH therapy included idiopathic isolated GH deficiency (n=5,162), 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 ug/kg/day 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 6,558 (94.7%) of participants. Ninety-three of the 6,558 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 [SMR]: 1.33, 95% CI: 1.08-1.64). 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 not 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). The authors noted that the analysis of factors associated with the increased mortality rate was limited by the small number of events in any demographic group or any particular cause of death. Due to the small number of deaths in this sample, conclusions cannot be drawn from these data on the impact of GH therapy on mortality risk. Additional data will be examined as they become available.

Growth Hormone Deficiency

Once a true GH deficiency has been established in association with clinical symptoms of GH deficiency, 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 GH deficiency. A few representative trials are discussed below.

Growth Hormone Deficiency in Children

In children with GH deficiency, treatment increases growth velocity and final height. Root and colleagues followed approximately 20,000 children for a period of 9 years as part of the National Cooperative Growth Study (NCGS). (5) Growth velocity improved compared to pre-treatment 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 scores that ranged from 1.3 to 2.5, depending on the specific underlying condition. If treatment is started at an early age, the majority of children can achieve a final height close to that expected from parental height. In a study of 1,258 patients in the Pfizer International Growth Database, the standard deviation for differences between the final height achieved and the midrange of predicted height from parental values ranged between -0.6 and +0.2, depending on the specific underlying condition. (6)

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. (7) 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. (8, 9) 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. (10) 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. (11-14)

Growth Failure Due to Prader-Willi Syndrome

The majority of 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 GH deficiency 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 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. (15) In 2012, the investigators published cognitive outcomes in children participating in this trial. (16) 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.

According to the drug prescribing information, GH therapy use has been associated with sudden death in children with Prader-Willi syndrome. (17) 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 (see Description section of this policy).

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 and colleagues in Scandinavia published an RCT evaluating GH therapy in 46 adults with genetically verified Prader-Willi syndrome. (18) 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. However, 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.

Section summary: For patients with documented GH deficiency 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 GH deficiency 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, GH deficiency is assumed, and GH replacement may be considered medically necessary without documentation of GH deficiency.

Conditions without Growth Hormone Deficiency

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. (19) 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.

Previously, in 2012, Hodson and colleagues published a Cochrane review of RCTs evaluating GH treatment in children with chronic kidney disease. (20) To be included in the review, trials needed to include children 18 years-old or younger who were diagnosed with chronic kidney disease and were pre-dialysis, on dialysis, or post-transplant. 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/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).

An example of an individual RCT is the trial by Hokken-Koelega and colleagues 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. (21) 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 per day) 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 to placebo. Long-term follow-up data on children in this and other Dutch RCTs (maximum of 8 years of treatment) were published in 2000. (22) GH treatment resulted in significant improvement in the height standard deviation score (SDS) compared to baseline scores (-<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 radiological signs of renal osteodystrophy.

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 human immunodeficiency virus (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"). (23) 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. (24) The authors reported improved waist/hip ratio and mid-thigh circumference.

GH Therapy for Turner’s 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’s syndrome is 58 inches (4 feet, 10 inches). Unlike Prader-Willi syndrome, growth hormone deficiency is not seen. The FDA approvals for GH were based on the results of randomized, controlled clinical trials that included final adult height as the outcome. For example, 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). (25)

In 2007, a Cochrane review identified 4 RCTs (total n=365) evaluating GH for treating Turner’s syndrome. (26) Studies included children who had not yet achieved final height, treated children for at least 6 months, and compared GH to placebo or no treatment. Only one 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 per year, 95% CI: 2 to 4 cm per year).

GH Therapy for 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. (27)

GH Therapy for 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). (25) 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. (28) This industry-sponsored open-label multicenter study was published by Blum and colleagues in 2007. (29) 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.

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. (30) 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).

One study that measured mortality was published by Knox and colleagues. (31) This was an RCT in 54 adult burn patients who survived the first 7 post-burn days. Those patients showing difficulty with wound healing were treated with recombinant human GH (rhGH) and compared to those healing at the expected rate with standard therapy. Mortality of rhGH-treated patients was 11% compared to 37% not receiving rhGH (p=0.027). Infection rates were similar in both groups. Moreover, Singh and colleagues 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%). (32) Another placebo-controlled trial found no benefit to GH with regard to length of hospitalization in 24 adult patients with severe burns. (33)

GH Therapy to Prevent 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. (34) Aili Low and colleagues found that GH treatment in severely burned children during hospitalization resulted in significantly greater height velocity during the first 2 years after burn compared to a similar group of untreated children. (35)

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. The FDA approval for Zorbtive was based on the results of a randomized, controlled, Phase III 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. (36) 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 (mean difference, MD, 1.66 kg, 95% CI: 0.69 to 2.63, p=0.0008).

Several published studies have also demonstrated improved intestinal absorption in short bowel syndrome patients receiving parenteral nutrition. (37, 38) However, studies have noted that the effects of increased intestinal absorption are limited to the treatment period. (38, 39) Specialized clinics may offer intestinal rehabilitation for patients with short bowel syndrome; GH may be one component of this therapy.

GH Use in Small for Gestational Age (SGA) Children

A meta-analysis of RCTs evaluating GH treatment for children born small for gestational age was published in 2009. (40) Four trials with a total of 391 children met the eligibility criteria (birth height or weight below 2 SDS and initial height less than 2 SDS). The GH dose ranged from 33 to 67 ug/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 ug/kg per day. 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…”

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, 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. (41-43)

GH Use in Children with Idiopathic Short Stature (i.e., without documented GH deficiency or underlying pathology)

Is GH effective at increasing the adult height of children with idiopathic short stature?

Several meta-analyses have been published. Most recently, Deodati and Cianfarani identified 3 RCTs and 7 non-randomized controlled trials. (44) To be included in the meta-analysis, studies needed to include pre-pubertal children with initial short stature (more than 2 SDs below the mean) and peak GH response greater than 10 ug/L. In addition, participants needed to have no previous growth hormone therapy and no comorbid conditions that could impair growth. Adult height was defined as a growth rate of less than 1.5 cm/year 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 a standard deviation score (SDS, also known as a z-score). The investigators considered a mean difference in height of more than 0.9 SD scores (about 6 cm) to be a satisfactory response to GH therapy. Only one of the RCTs was placebo-controlled, and that study had a high dropout rate (40% in the treated group and 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; mean difference=0.65 SDS (about 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 mean difference (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 evaluating GH therapy for idiopathic short stature in children and adolescents was published. (45) 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 to 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 to no treatment. Unlike the Deodati review described above, (2) studies were not required to report final adult height. Nine out 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 to untreated children. The weighted mean difference (WMD) was 2.84 (95% CI: 2.06 to 2.90). Five studies reported height SDSs, but there was heterogeneity among studies and 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.

Section summary: Recent systematic reviews have found that GH treatment may result in increases in height gain for children with idiopathic short stature, but the difference in height gain may not be clinically significant. The absolute difference in height in these studies is in the range of 3-4 cm, and children treated with GH remain below average in height, with heights that are between 1 and 2 standard deviations 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.

What is the 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 to controls. These studies are described briefly below:

In 2004, Ross and colleagues published findings on psychological adaptation in 68 children with idiopathic short stature without GH deficiency. (46) Children (mean age, 12.4 years) were randomized to receive GH therapy (n=37) or placebo (n=31) 3 times per week until height velocity decreased to less than 1.5 cm 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 and colleagues in the Netherlands published a trial in 2002 in which 40 prepubertal children with idiopathic short stature were randomly assigned to GH treatment (n=20) or a control group (n=20). (47) Parents and children were interviewed at baseline and at 1 and 2 years to obtain information on health-related quality of life (HRQOL) and children’s self-esteem. At the 2-year follow-up, satisfaction with current height was significantly associated with improvement in children’s reported health-related quality of life, 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 idiopathic short stature.

In 1996, Downie and colleagues examined the behavior of children without documented GH deficiency who were treated with GH due to idiopathic short stature. (48) Across measures of behavior, including IQ, self-esteem, self-perception, or parental perceptions of competence, there were no significant differences between the control and 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.

In summary 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 idiopathic short stature, and because this group of children is healthy (i.e., no identified pathology or hormone deficits) and thus should avoid unnecessary exposure to long-term medical treatment, GH treatment for children with idiopathic short stature 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 non-randomized 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 gonadotropin-releasing hormone (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. (49-51) 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 in order 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 growth hormone 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. (52, 53) 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. (52) 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 and colleagues 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. (54) 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 to 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 “investigational” 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 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 adults without organic pituitary disease. The policy regarding this off-label application is based on a 2001 TEC Assessment, (55) 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

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. (56) 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. (57) 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).

One of the RCTs was an industry-sponsored open-label study published by Stalvey and colleagues in 2012. (58) This study compared GH therapy to no treatment in prepubertal children with cystic fibrosis who were younger than 14 years-old. The eligibility criteria included height no more than 10th percentile for age and sex; children with documented GH deficiency 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 one were included in the safety analysis. Annualized height velocity at month 12 was 8.2 cm/yr (standard deviation [SD]: 2.1) in the treatment group and 5.3 cm/yr (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 to 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 of 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 air volume in 1 second (FEV1) (p<0.005) and forced vital capacity (FVC) (p<0.01). In the treatment group, mean forced expiratory volume in one second (FEV1) was 1,209 (SD: 451) at baseline, 1,434 (SD: 539) at 12 months, and 1,467 (SD: 568) at 18 months. This compared with 1,400 (SD: 495) at baseline, 1,542 (SD: 510) at 12 months, and 1,674 (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.

Section summary: GH treatment has been used in numerous conditions where there is not documented GH deficiency. For some of these conditions that are associated with growth failure, such as Turner’s syndrome, Noonan’s 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 small for gestational age and children with height that is more than 2.25 standard deviations 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 adverse effects, the use of GH treatment for these patients is considered not medically necessary.

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 investigational.

Ongoing Clinical Trials

Aromatase Inhibitors, Alone And In Combination With Growth Hormone In Adolescent Boys With Idiopathic Short Stature (ThrasherAI) (NCT01248416) (59): This open-label trial is randomly assigning adolescent boys with idiopathic short stature (equal or less than -2SD 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 75 participants, and the estimated date of study completion is October 2017.

Short Stature-Related Distress (NCT01246219) (60): 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) (61): 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 (PWS). (62) 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.

An Endocrine Society clinical practice guideline on adult growth hormone deficiency, updated in 2011, includes the following statements (63):

  • The Task Force recommends that GH therapy of GH-deficient adults offers significant clinical benefits in body composition and exercise capacity
  • The Task Force suggests that GH therapy of GH-deficient adults offers significant clinical benefits in skeletal integrity
  • The Task Force recommends after documentation of persistent GHD that GH therapy be continued after completion of adult height to obtain full skeletal/muscle maturation during the transition period

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. (64) 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. (65) 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. (66) 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 (AAP) published a document that recommended the following patient selection criterion for children with short stature not associated with classic GH deficiency: (67)

“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.”

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  43. Tanaka T, Satoh M, Yasunaga T et al. When and how to combine growth hormone with a luteinizing hormone-releasing hormone analogue. Acta Paediatr Suppl 1999; 88(428):85-8.
  44. Deodati A, Cianfarani S. Impact of growth hormone therapy on adult height of children with idiopathic short stature: systematic review. BMJ 2011; 342:c7157.
  45. Bryant J, Baxter L, Cave CB. Recombinant growth hormone for idiopathic short stature in children and adolescents. Cochrane Database Syst Rev 2009; (1):CD004440.
  46. Ross JL, Sandberg DE, Rose SR et al. Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo. J Clin Endocrinol Metab 2004; 89(10):4873-8.
  47. Theunissen NC, Kamp GA, Koopman HM et al. Quality of life and self-esteem in children treated for idiopathic short stature. J Pediatr 2002; 140(5):507-15.
  48. Downie AB, Mulligan J, McCaughey ES et al. Psychological response to growth hormone treatment in short normal children. Arch Dis Child 1996; 75(1):32-5.
  49. Adan L, Chemaitilly W, Trivin C et al. Factors predicting adult height in girls with idiopathic central precocious puberty: implications for treatment. Clin Endocrinol (Oxf) 2002; 56(3):297-302.
  50. Manasco PK, Pescovitz OH, Hill SC et al. Six-year results of luteinizing hormone releasing hormone (LHRH) agonist treatment in children with LHRH-dependent precocious puberty. J Pediatr 1989; 115(1):105-8.
  51. Walvoord EC, Pescovitz OH. Combined use of growth hormone and gonadotropin-releasing hormone analogues in precocious puberty: theoretic and practical considerations. Pediatrics 1999; 104(4 pt 2):1010-4.
  52. Pucarelli I, Segni M, Ortore M et al. Effects of combined gonadotropin-releasing hormone agonist and growth hormone therapy on adult height in precocious puberty: a further contribution. J Pediatr Endocrinol Metab 2003; 16(7):1005-10.
  53. Tato L, Saggese G, Cavallo L et al. Use of combined Gn-RH agonist and hGH therapy for better attaining the goals in precocious puberty treatment. Horm Res 1995; 44(suppl 3):49-54.
  54. Tuvemo T, Gustafsson J, Proos LA. Growth hormone treatment during suppression of early puberty in adopted girls. Acta Paediatr 1999; 88(9):928-32.
  55. Blue Cross and Blue Shield Association, Technology Evaluation Center (TEC). Recombinent Human Growth Hormone (GH) Therapy in Adults with Age-Related GH Deficiency. TEC Assessments 2001; Volume 16, Tab 11.
  56. Thaker V, Haagensen AL, Carter B et al. Recombinant growth hormone therapy for cystic fibrosis in children and young adults. Cochrane Database Syst Rev 2013; 6:CD008901.
  57. Phung O, Coleman CI, Baker EL et al. Recombinant human growth hormone in the treatment of patients with cystic fibrosis. Pediatrics 2010; 126(5):e1211-6.
  58. Stalvey MS, Anbar RD, Konstan MW et al. A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis. Pediatr Pulmonol 2012; 47(3):252-63.
  59. Sponsored by Nemours Children's Clinic. Aromatase Inhibitors, Alone And In Combination With Growth Hormone In Adolescent Boys With Idiopathic Short Stature (ThrasherAI) (NCT01248416). Available online at: www.clinicaltrials.gov. Last accessed July, 2013.
  60. Sponsored by Rabin Medical Center (Collaborator: Pfizer). Short Stature Related Distress (NCT01246219). Available online at: www.clinicaltrials.gov. Last accessed July, 2013.
  61. Sponsored by Assistance Publique - Hôpitaux de Paris. Severe Decrease of Growth Velocity in Children With Anorexia Nervosa.Therapeutic Trial of Growth Hormone (OREX) (NCT01626833). Available online at: www.clinicaltrials.gov. Last accessed July, 2013.
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  66. Cohen P, Rogol AD, Deal CL et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab 2008; 93(11):4210-7.
  67. American Academy of Pediatrics. Considerations related to the use of recombinant human growth hormone in children. Pediatrics 1997; 99:122-9.  
     

Codes

Number

Description

CPT 

96372

Therapeutic, prophylactic or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

ICD-9 Procedure 99.24 Injection of other hormone

ICD-9 Diagnosis 

042 Human immunodeficiency virus

 

253.2 

Pituitary hormone deficiency (anterior) 

 

253.3 

Growth hormone deficiency 

 

253.5 

Pituitary hormone deficiency (posterior) 

 

259.1 

Precocious sexual development and puberty 

 

579.3 

Short bowel syndrome 

  585.9

Chronic renal insufficiency 

  756.89 Other specified anomalies of muscle, tendon, fascia or connective tissue (includes SHOX deficiency with dyschondrosteosis)

 

764.90-764.99

Fetal growth retardation, unspecified (i.e., small for gestational age) code range

 

758.6 

Turner’s syndrome (includes SHOX deficiency with Turner’s syndrome) 

 

783.4 

Delayed development 

  783.43 Short stature (includes SHOX deficiency with idiopathic short stature)

 

042 

Human immunodeficiency virus 

 

799.4 

Cachexia 

 

759.81 

Prader-Willi syndrome 

 

941.30 – 941.39 

Burn of face, head, neck, full-thickness skin loss (third-degree burn not otherwise specified) code range 

 

943.30 – 943.39 

Burn of upper limb, except wrist and hands, full-thickness skin loss (third-degree burn not otherwise specified) code range 

 

944.30 – 944.38 

Burn of wrist(s) and hand(s) full-thickness skin loss (third-degree burn not otherwise specified) code range 

 

945.30 – 945.39 

Burn of lower limb(s); full-thickness skin loss (third-degree burn not otherwise specified) code range 

 

946.3 

Burns of multiple specified sites; full-thickness skin loss (third-degree not otherwise specified) 

 

949.3 

Burn, unspecified; full-thickness skin loss 

HCPCS 

J2941 

Injection, somatropin, 1 mg 

  J3490 Unclassified Drug

 

S9558 

Home injectable therapy; growth hormone, including administrative services, professional pharmacy services, coordination of care, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem 

ICD-10-CM (effective 10/1/14) E23.0 – E23.7 Hypofunction and other disorders of the pituitary gland; code range  
   E30.1 Precocious puberty  
   K91.2 Postsurgical malabsorption, not elsewhere classified (short bowel syndrome)  
   N28.9 Disorder of kidney and ureter, unspecified  
P05.00 – P05.9 Disorders of newborn related to slow fetal growth and fetal malnutrition; code range  
Q96.0 – Q96.9 span style="font-family: Arial, Helvetica;">Turner’s syndrome; code range  
    R62.0 – R62.59 Lack of expected normal physiological development in childhood and adults; code range  
   B20 Human Immunodeficiency virus  
   R64 Cachexia  
   Q87.1 Prader-Willi syndrome  
   T20.30xA- – T20.39xS Burn of third degree of head, face and neck; code range  
   T22.30xA - T22.39xS Burn of third degree of shoulder and upper limb, except wrist and hand; code range  
   T23.301A - T23.399S Burn of third degree of wrist and hand; code range  
   T24.301A- - T24.399S Burn of third degree of lower limb, except ankle and foot; code range  
    T25.311A - T25.399S Burn of third degree of ankle and foot; code range  
   T30.0  Burn of unspecified body region, unspecified degree  
ICD-10-PCS (effective 10/1/14)    ICD-10-PCS codes are only used for inpatient services. There are no ICD-10-PCS codes for drugs.  
   3E013VJ, 3E033VJ, 3E043VJ, 3E053VJ, 3E063VJ Administration, introduction, other hormone, percutaneous, code by body part (subcutaneous tissue, peripheral vein, central vein, peripheral artery, or central artery) 

Place of Service 

Home
Outpatient
Physician`s Office
 


Index

Growth Hormone Replacement Therapy, Recombinant Human
Human Growth Hormone Replacement Therapy, Recombinant
Precocious Puberty, Growth Hormone
Recombinant Human Growth Hormone Replacement Therapy  


Policy History

Date Action Reason
11/1/97 Add to Prescription Drug section New policy
02/15/02 Replace policy Policy updated and revised; new policy statement on GH for adults and small for gestational age children
05/15/02 Replace policy Policy revised; new policy statement on GH therapy for altered body habitus related to HIV (investigational)
10/9/03 Replace policy Policy revised; new policy statement on short stature children without GH deficiency (not medically necessary), additional discussion of laboratory tests used to define GH deficiency
12/17/03 Replace policy Literature review update; GH for Turner’s syndrome included in policy statement as may be medically necessary
07/15/04 Replace Policy Literature review update for the period of June 2003 through May 2004; added FDA precaution for growth hormone use in adults 65 and over to the policy guidelines; added investigational uses for precocious puberty, obesity, cystic fibrosis, idiopathic dilated cardiomyopathy, and juvenile idiopathic arthritis to the policy statement; added use of Zorbtive for treatment of short bowel syndrome to description and policy statement as may be medically necessary
12/14/05 Replace policy – coding update only CPT coding updated
07/20/06 Replace policy Literature review update; added chronic infectious disease to investigational policy statement on anabolic therapy for catabolic illness; and added chronic to investigational policy statement on treatment of juvenile idiopathic arthritis. Reference number 42 added; otherwise, policy statement unchanged
<10/13/2006 Local Policy Policy, Policy Guidelines, and Coding updated
06/12/08 Replace policy  Policy updated with literature search for Prader Willi syndrome, Noonan syndrome, and cystic fibrosis. Reference numbers 43 to 46 added. “Growth failure” added to medically necessary indication for Prader-Willi syndrome; Noonan syndrome changed to medically necessary indication; no other changes in policy statements. 
10/04/11 Replace Policy Policy updated with literature review, focusing on idiopathic short stature, genetic potential in children with tall parents and GH deficiency. References 1-5, 7, 32, 40-42 added; other references renumbered or reviewed. Treatment of children with “genetic potential” (i.e., those with tall parents) added as investigational indication.
11/10/11 Replace policy-correction only Numbering under Policy Guidelines section corrected
9/13/12 Replace policy Policy updated with literature review. Children with short stature due to SHOX (short stature homeobox-containing gene) deficiency added to medically necessary statement as correction (this is FDA-approved indication). In medically necessary statement, ‘patients’ with growth failure due to Prader-Willi syndrome changed to ‘children’ with growth failure due to Prader-Willi syndrome. References 1, 2, 4-14, 17-20, 23, 59-62 added; other references renumbered or removed.
9/12/13 Replace policy Policy updated with literature review through July 11, 2013. No change to policy statements. References 10, 16, 19, 30, 56, 61, 62 and 66 added; other references renumbered or removed.