BlueCross and BlueShield of Montana Medical Policy/Codes
Growth Hormone (GH)
Chapter: Drugs - Medical Benefit
Current Effective Date: September 24, 2013
Original Effective Date: September 22, 1993
Publish Date: June 24, 2013
Revised Dates: May 12, 2004; April 27, 2009, March 1, 2010, February 1, 2012; November 08, 2012; June 24, 2013
Description

Human growth hormone, also known as somatotropin, is synthesized in somatotropic cells of the anterior lobe of the pituitary gland.  Beginning in 1985, recombinant GH (rhGH or somatropin) has been marketed for a variety of FDA-labeled indications.  rhGH is also proposed for various non-labeled indications such as cystic fibrosis and treatment of older adults without documented GH deficiency. 

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 growth hormone (GH), GH was rationed to those children with classic growth hormone deficiency (GHD) as defined by a subnormal response (< 10 ng/ml) to GH provocation tests.  However, the ready supply of GH has created interest in expanding its use to short-stature children without classic GHD, often referred to as:

  • Partial GHD,
  • Neurosecretory GH dysfunction,
  • Constitutional delay in growth and development, or
  • Idiopathic short-stature (ISS). 

Classic GHD is suggested when there is an abnormal growth velocity (typically below the 10th percentile) or height is more than 2.0 SD 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 as outlined below:

  • Selection of patients to be tested,
  • Limitations in the laboratory testing for GH,
  • Establishment of diagnostic cutoffs for normal versus abnormal GH levels,
  • Availability of the laboratory tests to predict response to GH therapy,
  • Changes in growth velocity due to GH therapy,
  • Whether resulting final height is significantly improved, and
  • Whether improvement is clinically or emotionally significant for the patient.

There are many ethical considerations regarding GH therapy, most prominently the appropriate informed consent when therapy is primarily requested by the parent due to their particular psychosocial concerns regarding height.

The following table lists the approved FDA rhGH therapy drugs:

DOSING TABLE

NOTE:  Drug dosing recommendations in the Medical Policy follow FDA approved dosage in the product label.  A prescription for doses that exceed the product label must be accompanied by citation of clinical studies that support a higher dose regimen.

Drug Name:

Recommended FDA Labeled Dosage

Genotropin®

(somatropin recombinant)

Genotropin should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:

  • Pediatric dosing:  the recommended weekly dosages in milligrams (mg) per kilogram (kg) of body weight (given in divided doses six to seven times per week).
    1. 0.16 to 0.24 mg/kg/week.
    2. Prader-Willi Syndrome: 0.24 mg/kg/week.
    3. SGA: Up to 0.48 mg/kg/week.
    4. Turner Syndrome: 0.33 mg/kg/week.
    5. ISS: up to 0.47 mg/kg/week.
  • Adult GHD: Either a non-weight based or a weight based dosing regimen may be followed, with doses adjusted based on treatment response and IGF-I concentrations.
  • Non-weight based dosing: A starting dose of approximately 0.2mg/day (range, 0.15-0.30 mg/day) may be used without consideration of body weight, and increased gradually every one to two months by increments of approximately 0.1-0.2 mg/day.
  • Weight based dosing: The recommended initial dose is not more than 0.04 mg/kg/week; the dose may be increased as tolerated to not more than 0.08 mg/kg/week at four to eight week intervals.

Humatrope®

(somatropin recombinant)

Humatrope should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:

  • Pediatric dosing:  the recommended weekly dosages in milligrams (mg) per kilogram (kg) of body weight (given in divided doses six to seven times per week).
  1. Pediatric GHD: 0.18 to 0.30 mg/kg/week.
  2. Turner syndrome: Up to 0.375 mg/kg/week.
  3. ISS: Up to 0.37 mg/kg/week.
  4. Short-stature homeobox (SHOX) gene deficiency: 0.35 mg/kg/week.
  5. SGA: Up to 0.47 mg/kg/week.
  • Adult GHD: Either a non-weight based or a weight-based dosing regimen may be followed, with doses adjusted based on treatment response and IGF-I concentrations.
  • Non-weight based dosing: A starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used without consideration of body weight, and increased gradually every one to two months by increments of approximately 0.1-0.2 mg/day.
  • Weight-based dosing: The recommended initial daily dose is not more than 0.006 mg/kg (6 μg/kg); the dose may be increased to a maximum of 0.0125 mg/kg (12.5 μg/kg) daily.

Norditropin®

Or

Norditropin Nordiflex® (somatropin recombinant)

Norditropin should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:

  • Pediatric dosing:  the recommended weekly dosages in milligrams (mg) per kilogram (kg) of body weight (given in divided doses six to seven times per week).
  1. Pediatric GHD: 0.024 to 0.034 mg/kg/day.
  2. Noonan Syndrome: Up to 0.066 mg/kg/day.
  3. Turner Syndrome: Up to 0.067 mg/kg/day.
  4. SGA: Up to 0.067 mg/kg/day.
  • Adult GHD: 0.004 mg/kg/day to be increased as tolerated to not more than 0.016 mg/kg/day after approximately 6 weeks, or a starting dose of approximately 0.2 mg/day (range, 0.15 to 0.30 mg/day) increased gradually every one to two months by increments of approximately 0.1 to 0.2 mg/day.

Nutropin®

(somatropin rDNA orgin or somatropin recombinant)

Nutropin should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:

  • Pediatric GHD: a weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injection is recommended.  In pubertal patients, a weekly dosage of up to 0.7 mg/kg divided daily may be used.
  • Turner Syndrome:  a weekly dosage of up to 0.375 mg/kg of body weight divided into equal doses three to seven times per week by subcutaneous injection is recommended.
  • ISS:  a weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injection has been shown to be safe and efficacious, and is recommended.
  • Chronic Renal Insufficiency:  a weekly dosage of up to 0.35 mg/kg of body weight divided into daily subcutaneous injection is recommended.
  • Adult GHD: for weight-based dosing, the recommended dosage at the start of therapy is not more than 0.006 mg/kg given as a daily subcutaneous injection.  The dose may be increased according to individual patient requirements to a maximum of 0.025 mg/kg daily in patients under 35 years old and to a   maximum of 0.0125 mg/kg daily in patients over 35 years old.  Alternatively, taking into account more recent literature, a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used without consideration of body weight.  This dose can be increased gradually every one to two months by increments of approximately 0.1-0.2 mg/day, according to individual patient requirements based on the clinical response and serum IGF-I concentrations.

Omnitrope®

(somatropin recombinant)

Omnitrope should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:

  • Pediatric dosing:  the recommended weekly dosages in milligrams (mg) per kilogram (kg) of body weight (given in divided doses six to seven times per week).
    1. : 0.16 to 0.24 mg/kg/week.
    2. Prader-Willi Syndrome: 0.24 mg/kg/week.
    3. SGA: Up to 0.48 mg/kg/week.
    4. Turner Syndrome: 0.33 mg/kg/week.
    5. ISS: Up to 0.47 mg/kg/week.
  • Adult GHD: not more than 0.04 mg/kg/week (divided into daily injections) to be increased as tolerated to not more than 0.08 mg/kg/week); to be increased gradually every one to two months.

Saizen®

(somatropin rDNA orgin or somatropin recombinant)

Saizen should be administered subcutaneously (which is preferred, but intramuscular is acceptable) and injection sites rotated to avoid lipoatrophy:

  • Pediatric GHD:  The recommended weekly dosage is 0.18 mg/kg of body weight.  It should be divided into equal doses given either on three alternate days, six times per week or daily. 
  • Adult GHD: based on the weight-based dosing, the recommended dosage at the start of therapy is not more than 0.005 mg/kg given daily.  The dosage may be increased to not more than 0.01 mg/kg/day after four weeks.  Alternatively, taking into account more recent literature, a starting dose of approximately 0.2 mg/day (range, 0.15-0.3 mg/day) may be used without consideration of body weight.  This dose can be increased gradually every one to two months by increments of approximately 0.1-0.2 mg/day.

Serostim® (somatropin rDNA orgin or somatropin recombinant)

Serostim should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:

  • HIV-Associated Wasting or Cachexia:  the usual starting dose is 0.1 mg/kg daily up to 6 mg.  Based on weight range dosing, the recommendations are:
  1. >55kg (>121 lb) – 6 mg daily,
  2. 45-55 kg (99-121 lb) – 5 mg daily,
  3. 35-45 kg (75-99 lb) – 4 mg daily, or
  4. <35 kg (<75 lb) – 0.1 mg/kg daily

Tev-Tropin®

(somatropin rDNA orgin or somatropin recombinant)

Tev-Tropin should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:

  • Pediatric GHD:  A dosage of up to 0.1 mg/kg (0.3 IU/kg) of body weight administered three times per week.  

Valtropin®

(somatropin recombinant)

Valtropin should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:

  • Pediatric GHD:  The amount administered during the pivotal study described herein was 0.23 mg/kg of body weight/week (0.033 mg/kg/day).  Generally, the recommended dosage is 0.17-0.3 mg/kg of body weight/week.  The weekly dose should be divided into equal amounts given either daily or six days a week.
  • Turner Syndrome:  The amount administered during the pivotal study described herein was 0.37 mg/kg of body weight/week (0.053 mg/kg/day).  Generally, the recommended dose is up to 0.375 mg/kg of body weight/week.  The weekly dose should be divided into equal amounts given either daily or six days a week by subcutaneous injection.
  • Adult GHD:  Based on the pivotal study described herein, the recommended dosage at the start of therapy is 0.33 mg/day (or 0.1 mL of reconstituted solution) (equivalent to 0.005 mg/kg/day in a 66 kg adult) (six days/week) given as a subcutaneous injection.  The dosage may be increased according to individual patient requirements to a maximum of 0.66 mg/day (equivalent to 0.010 mg/kg/day in a 66 kg adult) (six days/week) after four weeks.  Alternatively, taking into account recent literature, a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used.  This dose can be increased gradually every one to two months by increments of approximately 0.1-0.2 mg/day, according to individual patient requirements based on the clinical response and serum IGF-I concentrations. 

Zorbtive™

(somatropin recombinant)

Zorbtive should be administered subcutaneously and injection sites rotated to avoid lipoatrophy:

  • Short Bowel Syndrome:  should be administered at a dose of approximately 0.1 mg/kg subcutaneously daily to a maximum of 8 mg daily for four weeks.

Policy
Prior authorization is recommended. To authorize, call Blue Cross and Blue Shield of Montana (BCBSMT) Customer Service at 1-800-447-7828 or fax your request to the Medical Review Department at 406-441-4624. A retrospective review will be performed if services are not prior authorized.

Medically Necessary

This is not an all inclusive listing of all growth hormone preparations.  Refer to the U.S. Food and Drug Administration (FDA) for all labeled indications of those growth hormones not listed on this policy. 

NOTE: Check contract or legislative provisions which may mandate benefits.

BCBSMT may consider recombinant human growth hormone (rhGH) therapy is addressed by indications and medically necessary when the following specific criteria are met, listed on the table below and when:

  • There are FDA approved label indications; or
  • The FDA has granted an Orphan Drug Designation to the drug; or
  • There is an off-label listing within a standard reference compendia (such as the United States Pharmacopoeia Drug Information [USPDI] or the American Society of Health Systems Pharmacists’ American Hospital Formulary [AHFS]).

NOTE:  Off-label use of any FDA approved drugs that are not included in the medical necessity table below is considered not medically necessary OR may be considered experimental, investigational and unproven when:

  • The FDA has determined its use to be contraindicated for a specific condition; or
  • The off-label uses cannot be validated by standard reference compendia or peer reviewed literature. 

NOTE:  Certain rhGH are self injectables and therefore may be covered under a pharmacy benefit plan rather than the medical benefits.

MEDICALLY NECESSARY TABLE

If the FDA approved indication is:

Then the criteria for review includes the following for medically necessary consideration:

Growth hormone deficiency (GHD), in children

  • Failed TWO provocative growth hormone (GH) stimulation tests, each with peak value < 10 ng/ml. Testing can be done with growth hormone releasing hormone, arginine, insulin, L-dopa, clonidine, or glucagon); OR
  • Documentation of GHD resulting from either 1) a destructive lesion of the pituitary, 2) a medical treatment, including but not limited to ablative pituitary radiation or surgery, or 3) trauma.

Supportive documentation for children with GHD:

  • Documentation of growth velocity under 5.0 cm/year with documentation of height at least 2.0 standard deviations (SD) below mean over one year or more or more than 1.5 SD sustained over two years.
  • Bone age as determined by standard x-ray techniques to be two years or more behind chronological age.

NOTE:  In children, GH therapy is typically discontinued when the growth velocity is less than 2.0 cm/year; when epiphyseal fusion has occurred; or when the height reaches the 5th percentile of adult height.

NOTE:  Once GHD has been established in childhood no further documentation of need is required through age 18.

Short-stature, in children

  • Height less than 3rd percentile for chronological age with chronic renal insufficiency; AND
  • Serum creatinine is greater than 1.5 mg/dL, or a creatinine clearance is less than or equal to 75 ml/minute per 1.73 m2.

NOTE:  In patients with chronic renal failure undergoing transplantation, GH therapy is discontinued at the time of transplant.

Growth hormone deficiency (GHD), in adults

  • Failed TWO provocative GH stimulation tests,  each with peak value < 5 ng/ml. Testing can be done with insulin and one of the growth hormone releasing hormones, arginine, L-dopa, clonidine, or glucagon; OR
  • Documentation of GHD resulting from either 1) a destructive lesion of the pituitary; 2) a medical treatment, including but not limited to ablative pituitary radiation or surgery; or 3) trauma. 

NOTE:  Insulin Provocation is the preferred test for confirming GHD in most adults.  It must be ONE of the TWO tests provided for documentation of GHD unless the test is contraindicated because the patient has history of seizures, coronary artery disease, or high risk of coronary artery disease.

NOTE:  Only about 25% of children with documented GHD will be found to have GHD when tested as adults.  Therefore, once adult height has been achieved, they should be re-tested ONE time as adults to determine if continuing GH replacement therapy is medically necessary.

NOTE:  When a diagnosis of GHD is established for an adult, and therapy with GH is initiated, documentation may be requested at one to two year intervals to demonstrate that the patient is obtaining measurable clinical benefit from GH therapy.

NOTE:  A physician should consider a trial of withdrawal of GH therapy for patients who do not have demonstrated clinical benefit.

Acquired immunodeficiency syndrome (AIDS) wasting

 

 

  • Weight loss greater than 10% of baseline weight that cannot be explained by a concurrent illness other than HIV infection; AND 
  • Patient is on concurrent antiviral medications. 

NOTE: GH therapy is discontinued when the loss is less than 10% of baseline weight loss.

Turner's syndrome

(No criteria).

Prader-Willi syndrome

Associated growth failure.

Noonan’s syndrome

Short-stature.

Severe burns, in children

 

  • 3rd degree burns to prevent growth delay, when the treatment begins during acute hospitalization; AND
  • Up to one year after the 3rd degree burn, because scar tissue may interfere with growth.

Severe burns, in adults

3rd degree burns requiring promotion of wound healing.

Short bowel syndrome

Patients receiving specialized nutritional support in conjunction with optimal management of short bowel syndrome, including dietary adjustments, enteral feedings, parenteral nutrition, and fluid and micronutrient supplements. 

NOTE:  For additional discussion of short bowel syndrome, see Medical Policy MED201.021, Intestinal Rehabilitation Therapy.

Not Medically Necessary

BCBSMT considers recombinant human growth hormone (rhGH) therapy not medically necessary, including but not limited to, the following conditions listed on the table below.

NOT MEDICALLY NECESSARY TABLE

If the FDA approved indication is:

Then the explanation for not medically necessary is:

 

Small for gestational age (SGA)

Pediatric patients born SGA who fail to show catch up growth by age two, as there are no established criteria for SGA 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 2.0 SD below mean.  Absence of catch-up growth was defined as a height velocity below 1.0 SD score, adjusted for age. 

Non-GHD with short-stature (idiopathic short-stature [ISS])

Pediatric patients who are non-GHD with short-stature (also known as ISS), as studies have failed to demonstrate a significant impact of height on psychosocial morbidity.  The American Academy of Pediatrics (AAP) has pointed out that there will always be a population of individuals considered short based on the normal distribution of height, regardless of how the bell-shaped curve may be altered by GH therapy. 

Partial GHD

Patients with partial GHD, as these patients do not meet the criteria required for GHD.  Further lab testing of children without classic GHD to diagnose partial GHD, or other abnormalities of GH secretion or bioactivity, is not considered medically necessary.  This includes overnight hospitalization of children for testing of spontaneous GH secretion.

Neurosecretory GH dysfunction

Patients with neurosecretory GH dysfunction, as these patients do not meet the criteria required for GHD.  Further lab testing of children without classic GHD to diagnose partial GHD, or other abnormalities of GH secretion or bioactivity, is not considered medically necessary.  This includes overnight hospitalization of children for testing of spontaneous GH secretion.

Advanced Member Notice of Financial Liability for Denied Services

When the criteria for coverage is not met, BCBSMT encourages all participating providers to have a member complete and sign an Advanced Member Notification (AMN) form, stating that BCBSMT will not cover this service, supply, device, or drug. If an AMN is signed prior to delivery of the service, participating providers can balance bill the member. If an AMN is not signed, participating providers are financially liable for the service and cannot balance bill the BCBSMT member for denied services. Services deemed Not Medically Necessary, or Investigational that are provided by an out-of-state (Montana) or Out-of-Network provider are the financial responsibility of the member regardless of a completed AMN.

Refer to the Advanced Member Notification medical policy for more information.  The AMN form is available at www.bcbsmt.com (Click on Providers and then Forms).

Investigational

All Other Indications

Experimental, investigational and unproven applications for rhGH therapy include, but are not limited to, the following:

  • Constitutional delay (lower than expected growth percentiles compared with their target height percentiles and delayed skeletal maturation when growth velocities and rates of bone age advancement are normal);
  • In conjunction with gonadotropin releasing hormone (GnRH) analogues as a treatment of precocious puberty;
  • GH therapy in older adults to counter the effects of aging (without proven GHD);
  • Anabolic therapy (except for AIDS), provided to counteract acute or chronic catabolic illness (e.g., surgery outcomes, trauma, cancer, chronic hemodialysis, chronic infectious disease) producing catabolic (protein wasting) changes in both adult and pediatric patients;
  • Anabolic therapy to enhance body mass or strength for professional, recreational, or social reasons;
  • Glucocorticoid-induced growth failure;
  • Short-stature due to Down’s syndrome;
  • Intrauterine growth retardation;
  • Treatment of altered body habitus (e.g., buffalo hump, lipodystrophy) associated with antiviral therapy in human immunodeficiency virus (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 advanced age or symptoms of aging;
  • Treatment of inflammatory bowel disease; OR
  • Treatment of children with “genetic potential” (i.e., lower than expected height percentile based on parents’ height).  

The following diagnostic tests for GHD are considered experimental, investigational and unproven:

  • 24 hour continuous monitoring of GH levels, OR
  • Serum levels of insulin-like growth factors (IGF or IGF-1) or insulin-like growth factor-binding protein (IGFBP).

NOTE:  Somatropin (or somatropin recombinant) manufactured as Accretropin™, Asellacrin 2®, Asellacrin 10®, Bio-Tropin®, Protropin®, and Crescormon® has been discontinued and is no longer on the market.

NOTE:  See Description for recommended FDA labeled dosing.

Federal Mandate

Federal mandate prohibits denial of any drug, device or biological product fully approved by the FDA as investigational for the Federal Employee Program (FEP).  In these instances coverage of these FDA-approved technologies are reviewed on the basis of medical necessity alone.

Rationale for Benefit Administration

This medical policy was developed through consideration of peer reviewed medical literature, FDA approval status, accepted standards of medical practice in Montana, Technology Evaluation Center evaluations, and the concept of medical necessity. BCBSMT reserves the right to make exceptions to policy that benefit the member when advances in technology or new medical information become available.

The purpose of medical policy is to guide coverage decisions and is not intended to influence treatment decisions. Providers are expected to make treatment decisions based on their medical judgment. BCBSMT recognizes the rapidly changing nature of technological development and welcomes provider feedback on all medical policies.

When using this policy to determine whether a service, supply or device will be covered, please note that member contract language will take precedence over medical policy when there is a conflict.

Rationale

The following discussion focuses on the most controversial aspects of growth hormone (GH) use.

Laboratory diagnosis of growth hormone deficiency (GHD):  Diagnosing growth hormone deficiency (GHD) in children remains an area of confusion and disagreement.  As a result, guidelines remain vague.  For example, both the 2003 American Association of Clinical Endocrinologists (AACE) guidelines and the 2000 consensus guidelines published by the Growth Hormone Research Society state that diagnosis is a multifaceted process involving clinical, auxological, radiological, and biochemical assessment.  These guidelines provide an informed discussion of various measures, but no proposal of specific criteria.

Regarding biochemical testing alone, there is little agreement on specific criteria within the pediatric endocrinology community.  Some of the reasons include:

  • GHD has different causes: total or relative lack of GH, secretion of abnormal GH, decreased levels of GH dependent growth factors (e.g., IGF-1).
  • There is continuity between absent and normal GH secretion during childhood, making it difficult to specify a cutoff value for GHD.
  • A variety of agents are available for provocative testing; however, there is a lack of well-designed, adequately powered studies comparing the agents most commonly used in pediatric populations.
  • Provocative testing reproducibility is poor.
  • Various provocative test agents may have adverse effects in general and in certain pediatric subpopulations and require experience, careful administration and monitoring and adequate emergency facilities.
  • Test protocols that administer two agents during a single test (e.g., glucagon-propanolol or arginine) are thought to result in fewer GH-sufficient children being falsely identified as GHD than single agent tests.
  • Although the use of two separate provocative tests has been proposed in the past, the many possible combinations have not been investigated and compared for accuracy or to determine the best combinations.
  • GH assays used to measure the outcome of provocative tests differ in the anti-GH antibodies used for detection and in the GH standards used for calibrating the assays.  As a result, cutoff values for deficiency should be defined for each assay and laboratory.
  • Age-adjusted, normative data for comparison is limited; collecting more data in normal populations is limited by ethical considerations due to possible adverse events.

These areas of uncertainty have led some investigators and clinicians to abandon the use of provocative testing as the sole diagnostic for GHD, and instead base diagnoses on a combination of clinical and diagnostic test information.  These often include:

  • IGF-1 testing as a screen.  However, approximately 30% of GHD patients have normal IGF-I and approximately 30% of short GH-sufficient children have low IGF-I.
  • IGF-I in combination with a provocative test.
  • Provocative testing.
  • Magnetic resonance imaging (MRI) - In general, sensitivity and specificity are moderate.  However, the presence either of an ectopic posterior pituitary lobe or the association of a hypoplastic pituitary stalk and a hypoplastic anterior pituitary lobe is highly predictive of GHD.  MRI is recommended for any pediatric patient with the provisional diagnosis of GHD.
  • Radiologic bone age.
  • Standard auxologic measurements such as height standard deviation (SD) score, height velocity, and comparison of predicted final height and mid-parental height.
  • Clinical features suggesting GHD or genetic conditions associated with severe short-stature.

However, it should be noted that for the purposes of this policy, relying on auxological measurements alone is inadequate to document GHD.  This policy is based on the premise that GH would be considered medically necessary as a replacement therapy for GHD, and not medically necessary when used as treatment of short-stature in the absence of GHD.  For example, as discussed further below, treatment of short-stature without accompanying GHD is generally considered not medically necessary due to the lack of a functional impairment.

GH therapy in short-stature children without documented GHD:  While GH therapy in patients with classic GHD is accepted, the use of GH in short-stature patients without GHD (as identified by standard provocation tests) is controversial.  The controversy is related to difficulties in laboratory diagnosis of GHD:

  • The lack of pretreatment factors, either laboratory or other criteria such as various measurements of height, skeletal maturity, etc., 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 one controlled trial that examined the behavior of children without documented GHD who were treated with GH due to idiopathic short-stature (ISS).

Across measures of behavior, including intelligence quotient, 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 five years of GH therapy, coming from a 1996 study.  The authors (Downie et al.) 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 Pediatrics (AAP) published a document that recommended the following patient selection criterion for children with short-stature (not associated with classic GHD):  “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 therapy in small for gestational age (SGA) children:  In 2001, one GH preparation (Genotropin) received FDA-approval for treatment of small for gestational age (SGA) children.  This FDA-approval was based on four randomized, open-label controlled clinical trials.  Patients were observed for 12 months before being randomized to receive 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 GH dosage of 0.48 mg/kg/wk, the patients' height improved from a baseline of -3.4 SD to -1.7 SD below the mean.  In contrast, in the control group the SD score improved to a lesser degree, from -3.1 to -2.9 SD below the mean.  The issues associated with this indication for GH are similar to those for other short-stature children without documented GHD.  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 SGA children, 0.48 mg/kg/week, is a supraphysiologic dose.  For example, in patients with documented GHD, 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 short-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-stature youths have either low self-esteem or a higher than average amount of behavioral or emotional problems.

For both SGA children and short-stature children, an additional strategy to achieve target adult heights is to combine GH therapy with gonadotropin-releasing hormone (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.

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 eight years of age in girls and nine years in boys.  Central precocious puberty is related to hypothalamic pituitary gonad activation, leading to increase in sex steroid secretion, which accelerates growth and causes premature fusion of epiphyseal growth plates, thus impacting final height.  Children with precocious puberty are often treated with GnRH analogs to suppress the pituitary gonad 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. 

In contrast, patients with a slowly progressive form in which the predicted height does not change after two 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 mid parental height.  GH may be offered to these patients in order to achieve the targeted adult height.  There have been no randomized controlled trials comparing final adult height in those treated with GnRH analogs alone versus GnRH analogs combined with GH therapy, and the largest case series includes 35 patients.  Case series suggest that GH is most commonly offered as an adjunct to GnRH analogs when the growth velocity drops below the 25th percentile for chronological age.

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 was treated with a combination of GnRH and GH, and 18 girls who refused treatment with adjunctive GH.  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.  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 two 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 above, the not medically necessary status of other applications of GH for non-GH deficient short-stature children is based on the absence of a functional impairment associated with a less than predicted final adult height.  While these same considerations may apply to using GH therapy as a component of therapy for precocious puberty, the experimental, investigational and unproven status of this indication is based on lack of final height data from controlled trials.

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 ft 10 inches).  Unlike Prader-Willi syndrome, GHD 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.  It should also be noted that earlier initiation of GH therapy might result in more significant increases in adult height.

GH therapy in older adults without documented GHD:  The GH secretion rate decreases by an estimated 14% per decade after young adulthood; mean levels in older adults are less than half those of a young adult.  However, mean GH levels in older adults are greater than age-matched adults with diagnosed GHD.  Older individuals experience changes in body composition, loss of muscle mass, and decreases in bone mineral density that are similar to changes seen in adults with biochemically verified GHD.  Based on these observations, GH therapy has been investigated in older adult without organic pituitary disease.  The policy regarding this off label application is based on a 2001 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) assessment, which offered the following observations and conclusions:

In 1998 the 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 GHD.  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 six small controlled trials with at least ten patients per treatment arm have examined the effect of GH therapy on older patients who may have partial GHD, 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.  Not all improvements are statistically significant; different methods of measuring body composition across trials may be affected by GH-induced changes in extra cellular fluid, and may not be comparable.

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.  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 (or lipodystrophy), include thinning of the face, thinning of the extremities, truncal obesity, breast enlargement or an increased dorsocervical fat pad ("buffalo hump").  However, there is minimal published literature regarding the use of GH for this indication.  Letters to the editors and small case series dominate the literature.  The largest case series was reported by Wanke and colleagues who treated ten HIV-infected patients (with fat redistribution syndrome) with GH for three months.  The authors reported improved waist/hip ratio and mid-thigh circumference.

GH therapy for severe burns:  Mortality was studied in a controlled trial of 54 adult burn patients who survived the first seven post-burn days.  Those patients showing difficulty with wound healing were treated with recombinant human growth hormone (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.  In a randomized, double-blind, placebo-controlled trial of 40 severely burned children, the length of hospital stay was reduced from a mean of 0.8 days per % total body surface area (TBSA) burned for the placebo group to 0.54 days per % TBSA burned for the treatment group (p<0.05).  For the average 60% TBSA-burned patient, this approximates a length of stay reduction from 46 to 32 days.  Singh et al. studied two groups of patients (n=22) with comparable third-degree burns; those who received GH had improved wound healing and lower mortality (8% vs. 44%).  Demling et al. found significantly improved weight retention and wound healing time with GH or oxandrolone compared to standard treatment in 36 adults with severe burns.

Two phase III double-blind randomized controlled trials of GH treatment in adults following cardiac or abdominal surgery, multiple traumas, or acute respiratory failure found increased in-hospital mortality rates in patients who received GH.  The potential for increased mortality prompted additional studies in critically burned pediatric patients.  Ramirez et al. retrospectively studied 263 pediatric burn patients.  Those treated with GH had no increase in mortality from matched patients who did not receive GH.

However, a randomized, controlled trial in 56 children with more than 40% TBSA found no benefit of GH alone compared to or in combination with propanolol.  Another placebo-controlled trial found no benefit to GH with regard to length of hospitalization in 24 adult patients with severe burns.

GH therapy to prevent growth delay in children with severe burns:  Children with severe burns show significant growth delays for up to three years after injury.  GH treatment in 72 severely burned children for one year after discharge from intensive care resulted in significantly increased height in a placebo-controlled, randomized, double-blinded trial.  One study reported found that GH treatment in severely burned children during hospitalization resulted in significantly greater height velocity during the first two years after the burn compared to a similar group of untreated children.

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 growth hormone 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 four week period had significantly greater reductions in the weekly total volume of intravenous parenteral nutrition required for nutritional support.  However, the effects beyond four weeks were not evaluated nor were the treatment location (inpatient vs. outpatient) identified. 

Several published studies have also demonstrated improved intestinal absorption in short bowel syndrome patients receiving parenteral nutrition.  However, studies have noted the effects of increased intestinal absorption are limited to the treatment period.  Specialized clinics may offer intestinal rehabilitation for patients with short bowel syndrome; GH may be one component of this therapy.  Inpatient intestinal rehabilitation is considered separately in another policy.

Other Indications:  GH therapy has been investigated for use in the treatment of cystic fibrosis, idiopathic dilated cardiomyopathy, and juvenile idiopathic arthritis.  No randomized clinical trials (RCTs) were identified to sufficiently demonstrate the appropriateness of GH therapy in these conditions.

Ding and colleagues randomized 48 patients with chronic severe hepatitis B to evaluate growth hormone with lactulose versus no growth hormone.  The authors noted clinical improvement in 90% of patients; however, this study focused on intermediate short-term outcomes and no conclusions can be drawn from the study.  Therefore, chronic infectious disease is added to the investigational coverage statement on anabolic therapy for catabolic illness.

2012 Update

The policy was updated on several topics: Prader-Willi syndrome, Noonan’s syndrome, Turner’s syndrome, cystic fibrosis, lipodystrophy, advanced aging, inflammatory bowel disease, ISS, short bowel syndrome, children with tall parents, and children with GHD, as a result of a search of peer reviewed literature through January 2012.

Safety of GH treatment:  The largest study published to date on safety of GH treatment includes data on 54,996 included in a postmarketing surveillance registry established by Genetech, Inc. (Bell, 2010).  The study from Bell et al. 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 GHD (42.5%), ISS (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 seven deaths were each due to a different cause.  Overall, intracranial malignancies of non pituitary 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% 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.

GH treatment for various indications

Prader-Willi Syndrome:  Use of GH therapy for patients with growth failure due to Prader-Willi syndrome is an FDA approved indication.  Most patients with this syndrome have hypothalamic dysfunction and GHD.  Numerous studies have shown patient improvements with use of GH.  For example, a recent randomized study reported by Fensten involving 42 infants and 49 children showed that GH treatment significantly improved height, body mass index (BMI), head circumference, and body composition (Fensten, 2008).  Recently, deaths have been reported in Prader-Willi patients who are being treated with GH.  A number of these deaths occurred in children with morbid obesity, respiratory or sleep disorders.  Airway obstruction has been hypothesized as a potential cause; however, the exact role of GH is not certain.  Because of this, many specialists now recommend sleep studies and correction of underlying airway obstruction before initiating GH treatment in these patients.

Questions have been raised about the value of testing for GHD before treatment in these patients.  The majority of patients with Prader-Willi syndrome are GH deficient.  A number of recent clinical studies on use of GH in Prader-Willi syndrome were reviewed.  In none of these studies were patients selected for treatment based on presence or absence of GH, nor were results reported separately for those with or without GHD (and thus no differential impact was noted).  One older study did describe a series of Prader-Willi syndrome patients treated with GH that were GH deficient (Lindgren, 2008).  However, the FDA approval is for those with Prader-Willi syndrome and growth failure, thus this “growth failure” indication is added to the policy statement.  Information from the product label indicates that the height SD score for Prader-Willi syndrome children in the clinical studies was -1.6 or less (height was in the 10th percentile or lower).

Noonan’s Syndrome:  In 2007, the FDA approved the use of GH (Norditropin) for treatment of short-stature in children with Noonan’s 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’s syndrome (FDA, 2012).

Turner’s Syndrome:  In 2007, a Cochrane review identified four RCTs (total n=365) evaluating GH for treating Turner’s syndrome (Baxter, 2007).  Studies included children who had not yet achieved final height, treated for at least six 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 two trials found that short-term growth velocity was greater in treated than untreated children (mean difference [MD], three cm per year, 95% CI: two to four cm per year).

Cystic Fibrosis:  Since the use of GH is not FDA approved for this indication, this use remains considered experimental, investigational and unproven.  A systematic review by Phung et al. identified ten controlled trials evaluating GH for treating patients with cystic fibrosis (Phung, 2010).  One study was placebo-controlled, eight 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 four weeks and in the other studies, duration of treatment ranged from six months to one 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 one 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 are a number of important research questions that must be answered; in particular, there is a need for high-quality studies on health outcomes.

Lipodystrophy:  Since the use of GH is not FDA approved for this indication, this use remains considered experimental, investigational and unproven (FDA, 2012).  The coverage statement is unchanged.  However, some studies have demonstrated the efficacy of GH treatment to reduce visceral adipose tissue and to improve peripheral fat wasting as part of body habitus changes and metabolic abnormalities commonly observed in HIV patients.  Macallan (2008) reported that if GH is effective in reducing visceral fat, the effects are short-lived. 

Advanced Aging:  Although advanced age or symptoms of aging are not among approved indications for GH therapy, rhGH and various GH-related products are aggressively promoted as anti-aging therapies.  Well-controlled studies of the effects of GH therapy in endocrinologically normal elderly subjects report some improvements in body composition and a number of undesirable side effects in sharp contrast to the major benefits of GH therapy in patients with GHD.  Since the use of GH is not FDA approved for this indication, this use is considered experimental, investigational and unproven (FDA, 2012).

Inflammatory Bowel Disease:  Since the use of GH is not FDA approved for this indication, this use remains experimental, investigational and unproven.  This coverage statement is unchanged.  Studies have not clarified patient selection or long-term use during GH treatment of patients with inflammatory bowel disease (FDA, 2012).

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 (Deodati, 2011).  Most recently, Deodati and colleagues identified three RCTs and seven non-RCTs.  To be included in the meta-analysis, studies needed to include pre-pubertal children with initial short-stature (more than two standard deviations [SD] 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 an SD score (SDS, also known as a z-score).  The investigators considered a mean difference in height of more than 0.9 SD scores (about six 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 three 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 seven non-randomized studies was -1.7 SDS for treated children and -2.1 SDS for untreated children.  The mean difference 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 (Bryant, 2009).  A total of ten 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 six months.  Three studies were placebo controlled and the other seven compared GH therapy to no treatment (Deodati, 2011).  Unlike the Deodati review described above, studies were not required to report final adult height.  Nine out of ten studies in the Cochrane review were short-term and reported intermediate outcomes.  A pooled analysis of three studies reporting growth velocity at one 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 ISS in the short-term but that evidence on GH’s effects on adult height is extremely limited.

In summary, recent systematic reviews have found that GH treatment may result in increases in height gain for children with ISS, but the difference in height gain may not be clinically significant.  The absolute difference in height in these studies is in the range of 3-4cm, and children treated with GH remain below average in height, with heights that are between one and two SDs 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 ISS?  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 ISS without GH deficiency (Ross, 2004).  Children (mean age, 12.4 years) were randomized to receive GH therapy (n=37) or placebo (n=31) three 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 one and two, but in year four, 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 ISS were randomly assigned to GH treatment (n=20) or a control group (n=20) (Theunissen, 2002).  Parents and children were interviewed at baseline and at one and two years to obtain information on health-related quality of life (HRQOL) and children’s self-esteem.  At the two 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 ISS.

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 ISS, 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 ISS is considered not medically necessary.

GH Use in Small for Gestational Age (SGA) Children:  A meta-analysis of RCTs evaluating GH treatment for children born SGA was published in 2009 (Maiorana, 2009).  Four trials with a total of 391 children met the eligibility criteria (birth height or weight below two SDS and initial height less than two 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 four 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; mean difference=0.9 SDS (5.7 cm), p<0001.  There was no difference in adult height between the two 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 SGA children and short-stature children, an additional strategy to achieve target adult heights is to combine GH therapy with 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 (Saggese, 1995; Pasquino, 2000; Tanaka, 1999).   

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 Optimal Management of Short Bowel Syndrome:  A 2010 Cochrane review identified five RCTs evaluating GH therapy for treating short bowel syndrome (Wales, 2010).  Studies evaluated GH with or without glutamine treatment.  The primary outcome was change in body weight.  A pooled analysis of three small trials (total n=30) found a statistically significant difference in weight change when patients were treated with GH or placebo (MD, 1.66 kg, 95% CI: 0.69 to 2.63, p=0.0008).

General Practice Guidelines and Position Statements

In 2010, the National Institute of Health and Clinical Excellence (NICE) in the U.K. issued guidance on human GH for growth failure in children (NICE, 2010).  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 four years, or
  • Short-stature homeobox (SHOX) gene deficiency.

In 2009, the American Association of Clinical Endocrinologists issued updated guidelines on GH use in growth hormone-deficient adults and transition patients (Cook, 2009).  Evidence-based recommendations include the following:

  • GHD is a well-recognized clinical syndrome in adults that is associated with significant comorbidities if untreated;
  • GH should only be prescribed to patients with clinical features suggestive of adult growth hormone deficiency and biochemically proven evidence of adult growth hormone deficiency; and
  • 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.

Coding

Disclaimer for coding information on Medical Policies          

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

042, 99.24, 253.2, 253.3, 253.5, 253.7, 259.1, 579.3, 593.9, 764.9, 758.6, 783.40, 783.41, 783.42, 783.43, 799.4, 759.81,  941.30 to 941.39, 942.30-942.39, 943.30 to 944.39, 945.30 to 945.39, 946.3, 949.3

ICD-10 Codes

B20, E23.0-E23.7, E30.1, K91.2, N28.9, P05.00-P05.9, Q87.1, Q96.0-Q96.9, R62.0-R62.59, R64, T20.30xA-T20.39xS, T22.30xA-T22.39xS, T23.301A-T23.399S, T24.301A-T24.399S, T25.311A-T25.399S, T30.0, 3E013VJ, 3E033VJ, 3E043VJ, 3E053VJ, 3E063VJ

Procedural Codes: 96372, J2940, J2941, S9558
References
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  14. Cuttler, L., Silvers, J.B., et al.  Short stature and growth hormone therapy:  a national study of physician recommendation patterns.  Journal of the American Medical Association (1996) 276(7):531-7.
  15. Downie, A.B., Mulligan, J., et al.  Psychological response to growth hormone treatment in short normal children.  Archives of Diseases in Childhood (1996 July) 75(1):32-5.
  16. Guidelines for the use of growth hormone in children with short stature.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program.  TEC Bulletin (1996 July 3) 13(7).
  17. FDA – Serostim or Zorbitive (somatropin recombinant) – Product Information, Label, Approval Letter, News Release.  Food and Drug Administration (1996 August 23).  Available at http://www.fda.gov (accessed – 2012 February 8).
  18. Recombinant Human Growth Hormone Replacement Therapy in Adults.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (1996 September) 11 (9).
  19. Recombinant Human Growth Hormone Therapy in Catabolic Illness.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (1996 September) 11(10).
  20. FDA – Saisen (somatropin recombinant) – Product Information, Label, Approval Letter, News Release.  Food and Drug Administration (1996 October 8).  Available at http://www.fda.gov (accessed – 2012 February 8).
  21. Pediatrics - Considerations Related to the Use of Recombinant Human Growth Hormone in Children.  American Academy of Pediatrics, Committee on Drugs and Committee on Bioethics Pediatrics (1997 January 1).  Available at http://pediatrics.aappublications.org (accessed on 2012 March 21).
  22. Lindgren, A.C., Hagenas, L., et al.  Effects of growth hormone treatment on growth and body composition in Prader-Willi syndrome: a preliminary report.  The Swedish National Growth Hormone Advisory Group.  ACTA Paediatrica – Supplement (1997 November) 423:60-2.
  23. Lo, J.C., Mulligan, K., et al.  Buffalo hump in men with HIV-1 infection.  Lancet (1998) 351(9106): 867-74.
  24. Invited Report of a Workshop: Consensus Guidelines for the Diagnosis and Treatment of Adults with Growth Hormone Deficiency: Summary Statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency.  The Journal of Clinical Endocrinology and Metabolism (1998) 83(2):379-81.
  25. Manasco, P.K., Pescovitz, O.H., et al.  Six-year results of luteinizing hormone releasing hormone (LHRH) agonist treatment in children with LHRH-dependent precocious puberty.  Journal of Pediatrics (1998 July) 115(1):105-8.
  26. Lo, J.C., Mulligan, K., et al.  “Buffalo hump” in men with HIV-1 infection.  Lancet (1998 March 21) 351(9106):867-70.
  27. Ramirez, R.J., Wolf, S.E., et al.  Growth hormone treatment in pediatric burns: a safe therapeutic approach.  Annals of Surgery (1998 October) 228(4):439-48.
  28. Singh, K.P., Prasad, R., et al.  Effect of growth hormone therapy in burn patients on conservative treatment.  Burns (1998 December) 24(8):733-8.
  29. Tanaka, T., Satoh, M., et al.  When and how to combine growth hormone with a luteinizing hormone-releasing hormone analogue.  ACTA Paediatrica Supplement (1999 February) 88(428):85-8.
  30. Demling, R.H.  Comparison of the anabolic effects and complications of human growth hormone and the testosterone analog, oxandrolone, after severe burn injury.  Burns (1999 May) 25(3):215-21.
  31. Takala, J., Ruokonen, E., et al.  Increased mortality associated with growth hormone treatment in critically ill adults.  New England Journal of Medicine (1999 September 9) 341(11):785-92.
  32. Tuvemo, T., Gustafsson, J., et al.  Growth hormone treatment during suppression of early puberty in adopted girls.  Swedish Growth Hormone Advisory Group.  ACTA Paediatrica (1999 September) 88(9):928-32.
  33. Walvoord, E.C., and O.H. Pescovitz.  Combined use of growth hormone and gonadotropin-releasing hormone analogues in precocious puberty: theoretic and practical considerations.  Pediatrics (1999 October) 104(4 Part 2):1010-4.
  34. Wanke, C., Gerrior, J., et al.  Recombinant human growth hormone improves the fat distribution syndrome (lipodystrophy) in patients with HIV.  AIDS (1999 October 22) 13(15):2099-13 
  35. Scolapio, J.S.  Effect of growth hormone, glutamine, and diet on body composition in short bowel syndrome; a randomized, controlled study.  Journal of Parenteral Enteral Nutrition (1999 November-December) 23(6):309-12; discussion 312-3.
  36. Consensus: Consensus Guidelines for the Diagnosis and Treatment of Growth Hormone (GH) Deficiency in Childhood and Adolescence: Summary Statement of the GH Research Society.  The Journal of Clinical Endocrinology and Metabolism (2000) 85(11):3990-3.
  37. FDA – Norditropin (somatropin recombinant) – Product Information, Label, Approval Letter, News Release.  Food and Drug Administration (2000 June 20).  Available at <http://www.fda.gov> (accessed – 2012 February 8).
  38. FDA – Norditropin Noriflex (somatropin recombinant) – Product Information, Label, Approval Letter, News Release.  Food and Drug Administration (2000 June 20).  Available at http://www.fda.gov (accessed – 2012 February 8).
  39. Pasquino, A.M., Pucarelli, I., et al.  Adult height in short normal girls treated with gonadotropin-releasing hormone analogs and growth hormone.  The Journal of Clinical Endocrinology and Metabolism (2000 February) 85(2):619-22.
  40. Szkudlarek, J., Jeppesen, P.B., et al.  Effect of high dose growth hormone with glutamine and no change in diet on intestinal absorption in short bowel patients: a randomized, double blind, crossover, placebo controlled study.  GUT (2000 August) 47(2):199-205.
  41. Hart, D.W., Herndon, D.N., et al.  Attenuation of posttraumatic muscle catabolism and osteopenia by long-term growth hormone therapy.  Annals of Surgery (2001 June) 233(6):827-34.
  42. Aili Low, J.F., Barrow, R.E., et al.  The effect of short-term growth hormone treatment on growth and energy expenditure in burned children.  Burns (2001 August) 27(5):447-52.
  43. Recombinant Human Growth Hormone Therapy in Adults with Age-Related GH Deficiency.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (2001 November) 16(11).
  44. Losada, F., Garcia-Luna, P.P., et al.  Effects of human recombinant growth hormone on donor-site health in burned adults.  World Journal of Surgery (2002 January) 26(1):2-8.
  45. Adan, L., Chemaitilly, W., et al.  Factors predicting adult height in girls with idiopathic central precocious puberty: implications for treatment.  Clinical Endocrinology (Oxford) (2002 March) 56(3):297-302.
  46. Couto-Silve, A.C., Adan, L., et al.  Adult height in advanced puberty with or without gonadotropin hormone releasing analog treatment.  The Journal of Pediatric Endocrinology and Metabolism (2001 March) 15(3):297-305.
  47. Theunissen, N.C., Kamp, G.A., et al.  Quality of life and self-esteem in children treated for idiopathic short stature.  Journal of Pediatrics (2002 May) 140(5):507-15.
  48. Hart, D.W., Wolf, S.E., et al.  Beta-blockers and growth hormone after burn.  Annals of Surgery (2002 October) 236(4):450-6; discussion 456-7.
  49. American Association of Clinical Endocrinologists, Medical Guidelines for Clinical Practice for Growth Hormone Use in Adults and Children, 2003 Update.  Endocrine Practice (2003 January-February) 9(1).
  50. Adamopoulos, S., Parissis, J.T., et al.  Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy.  European Heart Journal (2003) 24(24):2186-96.
  51. Bechtold, S., Ripperger, P., et al.  Growth hormone improves height in patients with juvenile idiopathic arthritis: 41year data of a controlled study.  Journal of Pediatrics (2003) 143(4):512-9.
  52. Schibler, A., von der Heiden, R., et al.  Prospective randomized treatment with recombinant human growth hormone in cystic fibrosis.  Archives of Disease in Childhood (2003) 88(12):1078-81.
  53. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for Growth Hormone Use in Adults and Children – 2003 Update.  Endocrine Practice (2003 January-February) 9(1):65-76.
  54. Seguy, D., Vahedi, K., et al.  Low-dose growth hormone in adult home parenteral nutrition-dependent short bowel syndrome patients: a positive study.  Gastroenterology (2003 February) 124(2):293-302.
  55. NICE – Growth Hormone Deficiency (Adults) - Human Growth Hormone (TA64).  Technology Appraisal from National Institute for Clinical Excellence (2003 August).  Available at <http://guidance.nice.org.uk> (accessed on 2012 March 21).
  56. Pucarelli, I., Segni, M., et al.  Effects of combined gonadotropin-releasing hormone agonist and growth hormone therapy on adult height in precocious puberty: a further contribution.  The Journal of Pediatric Endocrinology and Metabolism (2003 September) 16(7):1005-10.
  57. Darmaun, D., Hayes, V., et al.  Effects of glutamine and recombinant human growth hormone on protein metabolism in prepubertal children with cystic fibrosis.  The Journal of Clinical Endocrinology and Metabolism (2004) 89(3):1146-52.
  58. Albert, S.G., and A.D. Mooradian.  Low-dose recombinant human growth hormone as adjuvant therapy to lifestyle modifications in the management of obesity.  The Journal of Clinical Endocrinology and Metabolism (2004) 89(2):695-701.
  59. Ross, J.L., Sandberg, D.E., et al.  Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo.  The Journal of Clinical Endocrinology and Metabolism (2004) 89(10):4873-8.
  60. Ding, H.G., Shan, J., et al.  Combined human growth hormone and lactulose for prevention and treatment of multiple organ dysfunction in patients with severe chronic hepatitis B.  World Journal of Gastroenterology (2005) 11(19):2981-3.
  61. Growth Hormone Prior Authorization Criteria.  Prime Therapeutics (2006 February) 1-10.
  62. Molitch, M.E., Clemmons, D.R., et al.  Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline.  Clinical Endocrinology and Metabolism (May 2006) 91(5):1621-34.
  63. FDA – Omnitrope (somatropin recombinant) – Product Information, Label, Approval Letter, News Release.  Food and Drug Administration (2006 May 30).  Available at http://www.fda.gov (accessed – 2012 February 8).
  64. Mahan, J.D., Warady, B.A., et al.  Assessment and treatment of short stature in pediatric patients with chronic kidney disease: a consensus statement.  Pediatric Nephrology (July 2006) 21(7):917-30.
  65. Hardin, D.S., Adams-Huet, B., et al.  Growth hormone treatment improves growth and clinical status in prepubertal children with cystic fibrosis: results of a multicenter randomized controlled trial.  Journal of Clinical Endocrinology and Metabolism (2006 December) 91(12):4925-9.
  66. Baxter, L., Bryant, J., et al.  Recombinant growth hormone for children and adolescents with Turner’s syndrome.  Cochrane Database Systematic Review (2007) (3):CD003887.
  67. Bryant, J., Baxter, L., et al.  Recombinant growth hormone for idiopathic short stature in children and adolescents.  Cochrane Database Systematic Review (2007) (3):CD004440.
  68. Issues in Growth Hormone Therapy.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program.  TEC Bulletin.  (2007 March 6).
  69. FDA – Valtropin (somatropin recombinant) – Product Information, Label, Approval Letter, News Release.  Food and Drug Administration (2007 April 19).  Available at http://www.fda.gov (accessed – 2012 February 8).
  70. Hardin, D.S., Kemp, S.F., et al.  Twenty years of recombinant human growth hormone in children relevance to pediatric care providers.  Clinical Pediatrics (Philadephia) (2007 May) 46(4):279-86.
  71. Bartke, A.  Growth hormone and aging: a challenging controversy.  Clinical Interventions in Aging (2008) 3(4):659-65.
  72. Benedini, S., Terruzzi, I., et al.  Recombinant human growth hormone: rationale for use in the treatment of HIV-associated lipodystrophy.  BioDrugs (2008) 22(2):101-12.
  73. FDA – Accretropin (somatropin recombinant) – Product Discontinuance Information.  Food and Drug Administration (2008 January 23).  Available at http://www.fda.gov (accessed – 2012 February 8).
  74. Fensten, D.A., Wevers, M., et al.  Mental and motor development before and during growth hormone treatment in infants and toddlers with Prader-Willi syndrome.  Clinical Endocrinology (Oxford) (2008 June 68(6):919-25.
  75. Macallan, D.C., Baldwin, C., et al.  Treatment of altered body composition in HIV-associated lipodystrophy: comparison of rosiglitazone, pravastatin, and recombinant human growth hormone.  HIV Clinical Trials (2008 July-August) 9(4):254-68.
  76. Festen, D.A., de Lind van Wijngaarden, R., et al.  Randomized controlled GH trial: effects on anthropometry, body composition and body proportions in a large group of children with Prader-Willi syndrome.  Clinical Endocrinology (Oxford) (2008 September) 69(3):443-51.
  77. Denson, L.A.  Growth hormone therapy in children and adolescents: pharmacokinetic/pharmacodynamic considerations and emerging indications.  Expert Opinions on Drug Metabolism and Toxicology (2008 December) 4(12):1569-80.
  78. Cofrancesco, J., Freedland, E., et al.  Treatment options for HIV-associated central fat accumulation.  AIDS Patient Care and STDs (2009 January) 23(1):5-18.
  79. Maiorana, A., and S. Cianfarani.  Impact of growth hormone therapy on adult height of children born small for gestation age.  Pediatrics (2009 September) 124(3):e519-31.
  80. Cook, D.M., Yuen, K.C., et al.  American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients – 2009 update.  Endocrinology Practice (2009 September-October) 15 Supplement 2:1-29.
  81. Wales, P.W., Nasr, A., et al.  Human growth hormone and glutamine for patients with short bowel syndrome.  Cochrane Database Systematic Review (2010) (6):CD006321.
  82. Richmond, E., and A.D. Rogol.  Current indications for growth hormone therapy for children and adolescents.  Endocrine Development (2010) 18:92-108.
  83. Bell, J., Parker, K.L., et al.  Long-term safety of recombinant human growth hormone in children.  The Journal of Clinical Endocrinology and Metabolism (2010 January) 95(1):167-77.
  84. NICE – Human Growth Hormone (Somatropin) for the Treatment of Growth Failure in Children (Review) (TA188).  Technology Appraisal from National Institute for Clinical Excellence (2010 May).  Available at http://guidance.nice.org.uk (accessed on 2012 March 21).
  85. Takeda, A., Cooper, K., et al.  Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation.  Health Technology Assessment (2010 September) 14(42):1-209, iii-iv.
  86. Goulet, O., Dabbas-Tyan, M., et al.  Effect of recombinent human growth hormone on intestinal absorption and body composition in children with short bowel syndrome.  (2010 September-October) 34(5):513-20.
  87. Phung, O.J., Coleman, C.I., et al.  Recombinant human growth hormone in the treatment of patients with cystic fibrosis.  Pediatrics (2010 November) 126(5):e1211-26.
  88. Deodati, A., and S. Cianfarani.  Impact of growth hormone therapy on adult height of children with idiopathic short stature: systematic review.  British Medical Journal (2011) 342:c7157.
  89. Deodati, A., Peschiaroli, E., et al.  Review of growth hormone randomized controlled trials in children with idiopathic short stature.  Hormone Research in Pediatrics (2011) 76 Supplement 3:40-2.
  90. The Endocrine Society – Evaluation and Treatment of Adult Growth Hormone Deficiency.  And Endocrine Society Clinical Practice Guideline (2011).  Available at http://www.endo-society.org (accessed on 2012 March 21).
  91. Human Growth Hormone.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2011 October) Prescription Drug 5.01.06.
History
February 2012  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. 
November 2012 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.
June 2013 Policy language and formatting revised.  Title changed from "Human Growth Hormone" to "Growth Hormone (GH)".  Added HCPCs code J2940 and removed J3490.
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Growth Hormone (GH)