Policy Statements

Growth Hormone (GH), Growth Hormone Releasing Hormone (GHRH), and Growth Hormone Antagonists (Revised)

Aetna Clinical Policy; April 18, 2006 ; Number 170

Policy

Growth Hormone :

Aetna considers growth hormone (GH) medically necessary for treatment of members in the following diagnostic categories who meet the criteria set forth below:

Growth Hormone Deficiency in Children and Adolescents :
Aetna considers GH replacement medically necessary for children and adolescents with the following indications:
1. Idiopathic growth hormone deficiency:
  Aetna considers GH replacement medically necessary for children and adolescents with growth hormone deficiency (GHD) and growth failure who meet all of the following criteria:
  1. Member has failed to respond to at least two standard GH stimulation tests, defined as a serum GH level (peak level) of less than 10 nanograms per milliliter (ng/ml) (20 mU/liter), after stimulation with insulin, levodopa, arginine, propranolol, clonidine, or glucagon.* (However, one abnormal GH test is sufficient for children with defined CNS pathology, history of irradiation, multiple pituitary hormone deficiency (MPHD) or a genetic defect affecting the GH axis); and
  2. Appropriate imaging (magnetic resonance imaging (MRI) or computed tomography (CT)) of the brain with particular attention to the hypothalamic–pituitary region has been carried out to exclude the possibility of a tumor; and
  3. At least one of the following criteria is met:
    - Child has severe growth retardation with height standard deviation score (SDS) less than 3 SDS below the mean for chronological age and sex; or
    - Child has moderate growth retardation with height SDS between –2 and –3 SDS below the mean for chronological age and sex and decreased growth rate (growth velocity (GV)** measured over one year below 25th percentile for age and sex); or
    - Child exhibits severe deceleration in growth rate (GV** measured over 1 year –2 SDS below the mean for age and sex); or
    - Child has decreasing growth rate combined with a predisposing condition such as previous cranial irradiation or tumor; or
    - Child exhibits evidence of other pituitary hormone deficiencies or signs of congenital GHD (hypoglycemia, microphallus).
    Note : Given the above criteria, further laboratory testing of children without classic GHD to diagnose "partial" GHD, or other abnormalities of GH secretion or bioactivity, is considered not medically necessary. This includes overnight hospitalization of children for testing of spontaneous GH secretion.
    
    Note : Measurement of insulin-like growth factor I (IGF-I) is considered medically necessary to determine adequacy of growth hormone therapy in adults and children. However, the diagnosis of growth hormone deficiency should not rely solely on IGF-I measurements, but must be confirmed by provocative tests solely for growth hormone secretion. Measurement of IGF binding protein-2 (IGFBP-2), IGF binding protein-3 (IGFBP-3), and the acid labile subunit of IGF-I are considered experimental and investigational.
    
    Notes :
    
    * For persons with thyroid deficiency, Aetna only accepts results of GH secretion tests that are performed after thyroid deficiency is adequately treated because GH secretion may be subnormal merely as a result of hypothyroidism.
    
    ** Growth velocity (GV) should be tracked over at least one year.
2. Chronic renal insufficiency:
  Aetna considers GH replacement prior to renal transplantation medically necessary for children with chronic renal insufficiency and growth retardation who meet both of the following criteria:
  1. Child's nutritional status has been optimized, metabolic abnormalities have been corrected, and steroid usage has been reduced to a minimum; and
  2. At least one of the following criteria is met:
    - Child has severe growth retardation with height SDS less than 3 SDS below the mean for chronological age and sex; or
    - Child has moderate growth retardation with height SDS between –2 and –3 SDS below the mean for chronological age and sex and decreased growth rate (GV measured over one year below 25th percentile for age and sex); or
    - Child exhibits severe deceleration in growth rate (GV measured over one year –2 SDS below the mean for age and sex).
    Note : Consistent with established guidelines for children with chronic renal insufficiency after renal transplantation, Aetna does not consider resumption of growth hormone therapy medically necessary until at least 1 year after the transplant to allow time to ascertain whether catch-up growth will occur.
3. Turner's syndrome:
  Aetna considers GH replacement medically necessary for children with Turner's syndrome and growth retardation who meet all of the following criteria:
  1. The diagnosis of Turner’s syndrome is confirmed by chromosome analysis; and
  2. At least one of the following criteria is met:
    - Child has severe growth retardation with height SDS less than 3 SDS below the mean for chronological age and sex; or
    - Child has moderate growth retardation with height SDS between –2 and –3 SDS below the mean for chronological age and sex and decreased growth rate (GV measured over one year below 25th percentile for age and sex); or
    - Child exhibits severe deceleration in growth rate (GV measured over one year –2 SDS below the mean for age and sex).
4. Prader Willi syndrome:
  Aetna considers GH replacement medically necessary for children with Prader Willi syndrome and growth retardation who meet all of the following criteria:
  1. The diagnosis of Prader Willi syndrome is confirmed by appropriate genetic testing; and
  2. Child has GH deficiency; and
  3. At least one of the following criteria is met:
    - Child has severe growth retardation with height SDS less than 3 SDS below the mean for chronological age and sex; or
    - Child has moderate growth retardation with height SDS between –2 and –3 SDS below the mean for chronological age and sex and decreased growth rate (GV measured over one year below 25th percentile for age and sex); or
    - Child exhibits severe deceleration in growth rate (GV measured over one year –2 SDS below the mean for age and sex).
5. Small for gestational age (SGA) children
  Aetna considers growth hormone supplementation medically necessary for children born small for gestational age, and who meet all of the criteria below:
  1. Child was born small for gestational age, defined as birth weight or length 2 or more standard deviations below the mean for gestational age; and
  2. Child fails to manifest catch up growth by age 2 years, defined as height 2 or more standard deviations below the mean for age and sex.
  Note : Growth curves plotting growth from birth through age 3 should be submitted for evaluation.
6. Discontinuation of therapy:
  In children and adolescents, GH therapy will be considered not medically necessary if any of the following discontinuation criteria is met:
  1. Increase in height velocity is less than 2 cm total growth in one year of therapy; or
  2. Expected final adult height has been reached; or
  3. If there is a poor response to treatment, generally defined as an increase in growth velocity of less than 50% from baseline, in the first year of therapy. In children with Prader-Willi syndrome, evaluation of response to therapy should also take into account whether body composition (i.e., ratio of lean to fat mass) has significantly improved; or
  4. There are persistent and uncorrectable problems with adherence to treatment.
  Note : At completion of linear growth (that is, growth rate less than 2 cm/year), available guidelines indicate that GH treatment should be stopped for at least 3 months, and GH status should be re-assessed to determine whether continued GH treatment into adulthood is necessary. Aetna will reevaluate the member three or more months after discontinuation of GH therapy to determine if the member fulfills medical necessity criteria for GH treatment at adult doses as set forth below.
Growth Hormone Deficiency in Adults :
Aetna considers GH replacement medically necessary for adults who meet the following criteria:
1. Destructive lesions of the pituitary:
  Aetna considers GH treatment of adults with documented GHD medically necessary when all of the following criteria are met:
  1. Member has GH deficiency as a result of hypothalamic or pituitary disease (e.g., panhypopituitarism, pituitary adenoma, trauma, cranial irradiation, pituitary surgery) and at least one other hormone deficiency diagnosed (except for prolactin deficiency); and
  2. Member is already receiving adequate replacement therapy for any other pituitary hormone deficiencies; and
  3. Member has a severe GH deficiency, defined as a peak GH response of less than 9 mU/liter (3 ng/ml) during an insulin tolerance test or a cross-validated GH threshold in an equivalent test (growth hormone releasing hormone, arginine, or glucagon); and
  4. Member has a perceived impairment of quality of life (QoL), as demonstrated by a reported score of at least 11 in the disease-specific 'Quality of life assessment of growth hormone deficiency in adults' (QoL-AGHDA) questionnaire (see Figure 4 below).
  Aetna considers this treatment medically necessary for an initial 9 months, allowing for an initial 3-month period of GH dose titration, followed by a 6-month therapeutic trial period. Subsequent GH treatment is considered medically necessary only if, upon subsequent testing of the effect of this treatment, the member demonstrates a QoL improvement of 7 or more points in QoL-AGHDA score (see Figure 4 below).
2. Adults who were growth hormone deficient as children or adolescents:
  1. For adolescents and adults younger than age 25 years with childhood-onset growth hormone deficiency (including idiopathic isolated growth hormone deficiency (IIGHD) or multiple pituitary hormone deficiencies, including growth hormone (MPHD)) who have completed linear growth (growth rate less than 2 cm per year), GH treatment at adult doses is considered medically necessary only in those who have failed to respond to at least two standard GH stimulation tests, defined as a peak GH response of less than 9 mU/liter (3 ng/ml) during an insulin tolerance test and one other cross-validated GH test (growth hormone releasing hormone, arginine, or glucagon). For adults having a low IGF-1 (a marker of insulin response) concentration (standard deviation score less than –2), failure to respond to only one standard GH stimulation test is required. In these members, GH supplementation at adult doses is considered medically necessary until adult peak bone mass is achieved (between 25 and 30 years of age). Note: Consistent with available guidelines, Aetna requires, as a condition of continued authorization of GH therapy at adult doses, that GH therapy be stopped for at least 3 months after completion of linear growth (that is, growth rate less than 2 cm/year), and that GH status should be reassessed. As a condition of continued authorization, Aetna requires reassessment of GH status after GH treatment is stopped for at least 3 months before initiating GH supplementation at adult doses. Aetna will reevaluate the member three or more months after discontinuation of GH therapy to determine if the member fulfills medical necessity criteria for GH treatment at adult doses.
  2. For adults over age 25 years with childhood onset growth hormone deficiency (IIGHD or MPHD), GH treatment at adult doses is considered medically necessary if they meet all of the following criteria:
    - Member has failed to respond to at least two standard GH stimulation tests, defined as a peak GH response of less than 9 mU/liter (3 ng/ml) during an insulin tolerance test and one other cross-validated GH test (growth hormone releasing hormone, arginine, or glucagon). For members having a low IGF-1 (a marker of insulin response) concentrations (SDS less than –2), failure to respond to only one standard GH stimulation test is required; and
    - Member has a perceived impairment of quality of life (QoL), as demonstrated by a reported score of at least 11 in the disease-specific 'Quality of life assessment of growth hormone deficiency in adults' (QoL-AGHDA) questionnaire (see Figure 4 below).
3. Adults who develop growth hormone deficiency in early adulthood:
  1. GH treatment at adult doses is considered medically necessary for selected members who develop isolated GH deficiency (IIGHD or MPHD) in adolescence or early adulthood, after linear growth is completed but before the age of 25 years. GH treatment at adult doses is considered medically necessary only in those who have failed to respond to at least two standard GH stimulation tests, defined as a peak GH response of less than 9 mU/liter (3 ng/ml) during an insulin tolerance test and one other cross-validated GH test (growth hormone releasing hormone, arginine, or glucagon). For adults having a low IGF-1 (a marker of insulin response) concentration (SDS less than –2), failure to respond to only one standard GH stimulation test is required. In these members, GH supplementation at adult doses is considered medically necessary until adult peak bone mass is achieved (between 25 and 30 years of age).
  2. Following achievement of peak bone mass between 25 and 30 years of age, continued GH treatment is considered medically necessary for adults who meet all of the following criteria:
    - Member has a severe GH deficiency: GH treatment at adult doses is considered medically necessary only in those who have failed to respond to at least two standard GH stimulation tests, defined as a peak GH response of less than 9 mU/liter (3 ng/ml) during an insulin tolerance test and one other cross-validated GH test (growth hormone releasing hormone, arginine, or glucagon). (For adults having a low IGF-1 (a marker of insulin response) concentration (SDS less than –2), failure to respond to only one standard GH stimulation test is required); and
    - Member has a perceived impairment of quality of life (QoL), as demonstrated by a reported score of at least 11 in the disease-specific 'Quality of life assessment of growth hormone deficiency in adults' (QoL-AGHDA) questionnaire (see Figure 4 below).
4. AIDS-related wasting:
  Aetna considers GH supplementation to be medically necessary for HIV-infected persons with involuntary weight loss of greater than 10% of pre-illness baseline body weight or body mass index (BMI) less than 20 kg/m 2, in the absence of a concurrent illness or medical condition other than HIV infection that would explain these findings, and who have failed to adequately respond or are intolerant to anabolic steroids (e.g., Megace).
Dosage :
According to available guidelines, for the first 2–3 months dosage adjustments should be made after monthly assessments of serum levels of IGF-1, and in response to the presence of adverse effects, until a maintenance dose is achieved. As a condition of continued authorization, Aetna requires at least annual reassessment of serum levels of IGF-1 in adults and appropriate dosage adjustments, as GH requirements in adults may decrease with age.
Continued Authorization :
The continued medical necessity of growth hormone therapy is reviewed at least annually to determine whether growth hormone therapy continues to be medically necessary. The annual medical necessity review focuses on response to therapy, whether discontinuation criteria are met, whether there are any major changes in clinical status affecting the medical necessity of growth hormone supplementation, and verification that the person continues to follow up with the provider and receive appropriate reevaluations and care.
Growth Hormone for Short Bowel Syndrome :
Aetna considers GH supplementation to be medically necessary for persons with short bowel syndrome who depend on intravenous parenteral nutrition for nutritional support. Growth hormone treatment of short bowel syndrome for more than four weeks duration is considered experimental and investigational as administration of growth hormone for more than four weeks duration has not been adequately studied for this indication. There is insufficient evidence of the effectiveness of repeat courses of growth hormone for short bowel syndrome.
Contraindications :
Growth hormone therapy is considered experimental and investigational in persons with any of the following contraindications for which the safety of growth hormone therapy has not been established:
1. Persons with evidence of tumor activity. In persons with tumors, anti-tumor therapy must be completed before initiating growth hormone therapy; or
2. Critically ill persons (e.g., after complications following open heart or abdominal surgery, multiple trauma, acute respiratory failure or similar conditions); or
3. Persons with known hypersensitivity to growth hormone or to any of its excipients; or
4. Benign intracranial hypertension (BIH); or
5. Diabetic retinopathy; or
6. Women who are pregnant or lactating.
Experimental and Investigational Indications :
Aetna considers GH therapy to be experimental and investigational for the following indications:
1. Constitutional delay of growth and development
2. To promote growth of infants with intrauterine growth retardation or Russell-Silver syndrome
3. Skeletal dysplasias (e.g., achondroplasia, kyphomelic dysplasia)
4. Osteogenesis imperfecta
5. Down syndrome and other syndromes associated with short stature and increased susceptibility to neoplasms (e.g., Bloom syndrome, Fanconi syndrome)
6. "Somatopause" in older adults
7. Infertility
8. Chronic catabolic states, including respiratory failure, pharmacologic glucocorticoid administration, and inflammatory bowel disease
9. Burn injuries
10. Obesity/morbid obesity
11. Hypophosphatemia (e.g., hypophosphatemic rickets)
12. Muscular dystrophy
13. Cystic fibrosis
14. Noonan syndrome
15. Spina bifida
16. Juvenile rheumatoid arthritis
17. Osteoporosis
18. Post-traumatic stress disorder
19. Depression
20. Hypertension
21. Corticosteroid-induced pituitary ablation
22. Precocious puberty
23. Chronic fatigue syndrome
24. Crohn’s disease.
Note : Growth hormone therapy will be considered medically necessary for persons who meet medical necessity criteria; even if they are also diagnosed with a co-morbid medical condition for which growth hormone therapy is considered not medically necessary or experimental and investigational. For example, growth hormone therapy would be considered medically necessary for a child with Noonan syndrome (an experimental and investigational indication) if the child was also severely growth hormone deficient according to the criteria set forth above.
Other Indications :
Note : Aetna does not consider idiopathic short stature a disease or injury. Accordingly, coverage would not be available under most plans, which provide coverage only for treatment of injury or disease. Please check benefit plan descriptions for details.
Growth Hormone Releasing Hormone (GHRH) :
Aetna considers GHRH (sermorelin acetate, Geref) medically necessary for members who meet the selection criteria for treatment for growth hormone above, or when GHRH is used as a diagnostic aid in evaluating pituitary function.
Pegvisomant (Somavert) :
Aetna considers pegvisomant (Somavert) medically necessary for the treatment of acromegaly in members who have had an inadequate response to surgery and/or radiation therapy and/or other medical therapies, or for whom these therapies are inappropriate.

Background

These criteria are based on evidence-based guidelines on growth hormone supplementation from the National Institute of Clinical Excellence (NICE, 2002). Growth hormone (GH) has been approved by the U.S. Food and Drug Administration (FDA) for treatment of GH deficiency (GHD) in both children and adults, short stature associated with chronic renal insufficiency (CRI) before renal transplantation, short stature in patients with Turner syndrome (TS), HIV-associated wasting syndrome in adults, idiopathic short stature, and treatment of children born small for gestational age (SGA) who fail to manifest catch-up growth.

GH therapy in adults :

Studies have shown that over 90 percent of adults diagnosed with growth hormone deficiency have overt pituitary disease, which is usually caused by a pituitary adenoma or by surgery or radiation therapy for a pituitary adenoma.

The syndrome of GHD characteristically manifests with deficiencies in bone density, reduction in muscle strength and exercise tolerance, decreases in vitality and energy, emotional lability, feelings of social isolation, and increases in body fat and higher serum lipid concentrations.

The usefulness of GH treatment in adults with pituitary disease who have completed their statural growth is based on the role of GH in increasing bone density and in improving mood and motivation. There is some evidence to suggest that growth hormone therapy improves cardiovascular risk factors and increases bone mineral density (Ball, 2002). A Committee convened by the National Institute of Clinical Excellence (2003) concluded, however, that it was uncertain what impact GH treatment had on the longer-term clinical outcomes and mortality related to cardiovascular risk factors and changes in bone mineral density. In addition, there are other more effective, better established and less costly therapies to reduce cardiovascular risk factors and increase bone mineral density.

The NICE Committee concluded that a trial of GH treatment could be recommended for adults with GH deficiency who have a severe perceived impairment of QoL as demonstrated by a reported score of at least 11 in QoL-AGHDA (NICE, 2003). The Committee agreed that the QoL-AGHDA questionnaire (see Figure 4 of Appendix) is the best available evaluation tool for the assessment of both baseline QoL and the effect of treatment in adults with GH deficiency. Upon examination of available evidence, the Committee found that the subgroup of adults with GH deficiency for whom treatment may be clinically justified are those who have an improvement in QoL equivalent to an absolute change in their baseline QoL-AGHDA score of at least 7 points. The Committee stated that reassessment of the need for GH replacement should take place after a trial treatment period of 9 months (3 months for dose titration and 6 months for assessment of response). For GH treatment to continue after this trial period, it should be necessary to demonstrate a sustained improvement in QoL.

NICE recommended that adults with childhood GHD must be retested as adults before long-term GH replacement is instituted, because some GH-deficient children are found to be GH sufficient in adulthood (NICE, 2003).

Growth hormone levels continue to decline through adulthood, and the proportion of adults who may be considered growth hormone deficient increases with age. Some investigators have claimed that idiopathic growth hormone deficiency in adults is common and that most cases of idiopathic adult-onset growth hormone deficiency go undetected. These investigators have promoted growth hormone supplementation as a "rejuvenation" treatment for aging adults with age-related declines in growth hormone levels. Clinical studies of elderly persons with relatively low levels of endogenous growth hormone have shown small increases in lean body mass and bone mass, as well as improvements in plasma lipid profile with growth hormone supplementation. However, the long-term oncogenic effects and other potential adverse consequences of growth hormone supplementation in adults with idiopathic growth hormone deficiency are unknown. In addition, improvements in lean body mass, bone mass, and plasma lipid profile may be better achieved with other treatments in adults with idiopathic growth hormone deficiency.

According to NICE, the diagnosis of GHD in adult patients requires provocative testing of GH secretion (NICE, 2003). Random samples of GH are usually meaningless. In most academic medical centers, the insulin tolerance test (ITT) has been the validated study of choice. However, the literature indicates the test has an inherent risk of profound hypoglycemia, and is contraindicated in patients with abnormal electrocardiographic findings, with a history of ischemic heart disease or cerebrovascular disease, or with seizure disorders. According to available guidelines, the ITT is not generally recommended for patients older than 65 years of age.

In adults, the GH response to insulin-induced hypoglycemia is dependent on age, weight, and sex hormones, but most normal adults tested will have a peak GH secretion above 3 ng/mL (when GH is measured in a polyclonal competitive radioimmunoassay). Thus, values less than 3 ng/mL are considered indicative of GHD. In children and adolescents, in whom secretion may be more robust and GH effects on growth may require higher levels of secretion than in older patients, values below 10 ng/mL are considered inadequate.

In patients in whom insulin-induced hypoglycemia is contraindicated or unsafe or where appropriate testing arrangements are unavailable, the literature states that alternatives to ITT should be used. Information is now emerging that intravenously administered arginine, either alone or in combination with GH-releasing hormone (GHRH), may be useful. When only intravenously administered arginine is used, cutoff values for a normal response are similar to those expected with ITT. When it is used in combination with GHRH, the response may be augmented and the cutoff level is somewhat higher (9 to 10 ng/mL). Available literature suggests tests that use of glucagon, propranolol, or levodopa has a lesser established diagnostic value in comparison to ITT. Although useful as a diagnostic procedure in children, the literature states that a test that uses clonidine is of dubious value for the diagnosis of GH deficiency in adults. In adults with a history of hypothalamic pituitary disease or cranial irradiation, generally only one provocative test of GH secretion is needed (NICE, 2003). In adults with childhood onset isolated GH deficiency (no evidence of hypothalamic pituitary abnormality or cranial irradiation), two diagnostic tests should be recommended, except for those having low insulin-like growth factor-1 (1GF-1) (a marker of GH response) concentrations (standard deviation score less than -2) who may be considered for one test (NICE, 2003).

Although serum IGF-I concentrations are related to GH adequacy, accepted guidelines state that the diagnosis of GHD should not rely simply on IGF-I measurements but should be confirmed by provocative tests solely for GH secretion.

In adults with GHD, the FDA-approved labeling states that the starting dosage of GH should be very low (0.1 to 0.4 mg/day). The product labeling further states that this dose should be increased gradually on the basis of clinical and biochemical responses assessed at monthly intervals. The biochemical marker generally relied upon for GH is the IGF-I level in serum. Values of IGF-I should be maintained in the normal age- and sex-adjusted range. The literature indicates that the dose may be increased, on the basis of individual patient requirements, to a maximum of 1.75 mg daily in patients younger than 35 years of age, and to a maximum of 0.875 mg daily in patients older than 35 years of age. Of note, this dose is substantially less than GH replacement doses in children and adolescents, in whom the dose is based on weight.

The FDA has approved the use of growth hormone (Zorbtive, Serono Inc., Rockland, MA) for the treatment of short bowel syndrome in patients receiving specialized nutritional support. According to the FDA-approved labeling, Zorbtive should be used in conjunction with optimal management of short bowel syndrome. Specialized nutritional support may consist of a high carbohydrate, low-fat diet, adjusted for individual patient requirements and preferences. Nutritional supplements may be added according to the discretion of the treating physician. Optimal management of short bowel syndrome may include dietary adjustments, enteral feedings, parenteral nutrition, fluid and micronutrient supplements, as needed. The FDA approval of Zorbtive was based on the results of a randomized, double-blind, controlled, parallel-group Phase III clinical study of growth hormone in subjects with short bowel syndrome (SBS) who were dependent on intravenous parenteral nutrition (IPN) for nutritional support. The primary endpoint was the change in weekly total IPN volume defined as the sum of the volumes of IPN, supplemental lipid emulsion (SLE), and intravenous hydration fluid. Subjects received either placebo with the nutritional supplement, glutamine (n=9), growth hormone without glutamine (n=16) or growth hormone with glutamine (n=16). All 3 groups received a specialized diet. Following a two-week equilibration period, treatment was administered in a double-blind manner over a further period of four weeks. The dosing of growth hormone was approximately 0.1 mg/kg/day for 4 weeks. Mean reductions in IPN volume in each patient group were significantly greater in both the group treated with growth hormone (reduction of 2.1 liter per week compared to placebo plus glutamine) and the group treated with growth hormone plus glutamine (reduction of 3.9 liter per week compared to placebo plus glutamine) than in group treated with placebo plus glutamine. According to the FDA-approved labeling, Zorbtive should be administered to patients with short bowel syndrome (SBS) at a dose of approximately 0.1 mg/kg subcutaneously daily to a maximum of 8 mg daily. Administration at doses higher than 8 mg per day or for more than 4 weeks has not been adequately studied. According to the FDA-approved labeling, injections should be administered daily for 4 weeks. The FDA notes that the safety and effectiveness of Zorbtive in pediatric patients with short bowel syndrome has not been established.

According to available guidelines, GH therapy is contraindicated in patients with active malignant disease, benign intracranial hypertension (BIH), and proliferative or pre-proliferative diabetic retinopathy. Potential for childbearing is not a contraindication, but accepted guidelines caution that GH therapy should be discontinued when pregnancy is confirmed. The guidelines further caution that GH should not be used in critically ill patients who have acute catabolism. GH therapy is also contraindicated in persons with hypersensitivity to GH or its excipients.

GH therapy in children :

The FDA has approved GH for use in the following pediatric conditions: growth hormone deficiency, Turner syndrome, chronic renal insufficiency before transplantation, and children born small for gestational age. An advisory committee to the FDA also recommended approval of growth hormone for children with idiopathic short stature.

An assessment conducted for the National Institute of Clinical Excellence (2001) suggests the following criteria be used to define subnormal growth in children with growth hormone deficiency:

Severe growth retardation with height standard deviation score (SDS) for sex and chronological age less than 3 SDS below the mean; or
Moderate growth retardation with height SDS for sex and chronological age between –2 and –3 SDS below the mean and decreased growth rate (growth velocity (GV) below 25th percentile for age and sex); or
Severe deceleration in growth rate (GV below 3rd percentile for age and sex); or
Decreasing growth rate combined with a predisposing condition such as previous cranial irradiation; or
Evidence of other pituitary hormone deficiencies or signs of congenital GHD (hypoglycemia, microphallus).

In addition, retardation of bone maturation is found in most cases of subnormal growth.

Diagnosis of GHD in children is confirmed by measurements of GH secretion, commonly in several samples following stimulation by a provocative agent such as insulin or clonidine (NICE, 2001). The literature states that the standard method of assessing growth hormone secretion in children is to measure the serum growth hormone response to insulin and other stimuli. Another method is to make frequent measurements of serum growth hormone during the day and night, but this is no more effective than the standard method for detecting growth hormone deficiency. Formerly, the diagnosis of growth hormone deficiency in children was based on a peak serum growth hormone concentration of 5 ng/mL or less in response to a provocative test, but a peak serum growth hormone concentration of less than 10 ng/mL is now considered abnormal. However, because the available growth hormone assays have not been standardized, the literature states that the cutoff value of less than 10 ng/mL is of limited usefulness, especially in borderline cases. Instead, accepted guidelines indicate the diagnosis should be based on very short height, as defined by the standard-deviation score (more than 2.0 standard deviations below the mean height for normal children of the same age), delayed bone age, poor growth velocity (less than the 25 th percentile), and predicted adult height substantially below the mean parental height. When used in conjunction with these measures, however, the guidelines suggest a peak serum growth hormone value of less than 10 ng/mL in response to stimulation is a reasonable definition of growth hormone deficiency, with values less than 5 ng/mL reflecting the most severe deficiency.

If thyroxine is insufficient, then the literature indicates tests of GH secretion should be postponed until the thyroid deficiency is adequately replaced because GH secretion may be subnormal merely as a result of the hypothyroidism. If GHD is suspected in a peripubertal person with a growth pattern that resembles constitutional delay of growth and development, sex steroid priming before testing of GH secretion has been recommended by some investigators.

Other markers of growth hormone secretion, such as concentrations of serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3), are not consistently abnormal in children with growth hormone deficiency.

Available literature states that growth hormone stimulation tests and indirect measures of determining endogenous growth hormone secretion (measurement of serum IGF-1 and IGFBP-3 or urinary GH) are often subject to questionable specificity, false failure rates, and lack of published age- and sex-specific normal ranges. Due to the inadequacies of these tests, a subnormal growth velocity often becomes the deciding factor in choosing to initiate growth hormone therapy. However, available literature indicates that measurement of short-term growth velocity is unreliable in predicting future growth. Growth velocity during the autumn and winter may be lower than that during the rest of the year by more than 2 cm/yr. and may be normal if less than 2.5 cm/year during these cooler seasons. Therefore, for valid measurements, accepted guidelines provide that growth velocity should be tracked over an entire year.

Because of its pronounced anabolic effects, GH is contraindicated in children with an active malignant condition. There is controversy over whether it is safe to administer growth hormone to children in the year or two following treatment for leukemia, medulloblastomas, ependymomas, or other tumors.

GH treatment in children with childhood-onset GHD is generally begun with a dosage of GH of 0.15 to 0.3 mg/kg per week given six or seven times weekly. A maintenance dosage of up to 0.30 mg/kg of body weight is frequently recommended. Treatment is continued until the handicap of short stature is ameliorated, until epiphyseal closure has been recorded, or until the patient is otherwise no longer responding to GH treatment.

Turner syndrome: Turner syndrome (TS), which occurs in 1 in every 2000 live born girls, is due to abnormalities or absence of an X chromosome and is frequently associated with short stature, which may be ameliorated with GH treatment. Because growth in height is variable in patients with Turner syndrome, literature suggest that the decision whether to treat with GH and the timing of such treatment should be made on the basis of each patient's height and growth velocity. Treatment is often initiated when the standard deviation score for height decreases to less than 2 standard deviations below the mean.

Growth failure associated with TS is thought to be multifactorial, with one of the factors being reduced sensitivity to GH, rather than decreased GH levels. Therefore, supra-physiological doses of GH are required for treatment in children with TS (NICE, 2002). According to the available literature, treatment is often initiated with GH doses higher than those used in treating GHD; the usual dose of GH for TS is 0.045-0.050 mg/kg/day. Several studies suggest that statural growth may be optimized by concomitant treatment with oxandrolone in a daily dose of 0.0625 mg/kg.

Prader-Willi syndrome: Prader-Willi syndrome (PWS) consists of hypothalamic obesity, short stature, developmental delay, hypogonadotropic hypogonadism, small hands and feet, and hypotonia. The hypothalamic disorder may result in impaired GH secretion in some patients. Studies have shown that GH appears to have beneficial effects on growth velocity of pediatric patients with Prader-Willi syndrome. Clinical studies have also shown that growth hormone supplementation in PWS has a positive impact on body composition, with increases in lean mass and decreases in percent body fat. The FDA has approved Genotropin brand of growth hormone for the “long-term treatment of pediatric patients who have growth failure due to Prader-Willi syndrome.” A number of randomized controlled clinical studies have reported significant increases in height velocity in PWS children treated with growth hormone. One uncontrolled study has reported on final height in a small group of treated children with PWS. The study reported final height of 170 cm in males and 159 in females. These heights are well within the normal range. Presuming a treatment effect based on the change in standard deviation (SD) from the start of treatment to the completion of treatment, there was a change of 1.64 SD. Converting this SD improvement to cm in adult height, this corresponds to treated males being approximately 11 cm and treated females being approximately 9.8 cm taller than the presumptive height of untreated children.

Children with Prader-Willi syndrome are considered to have a hypothalamic disorder, and thus GH therapy is intended to replace physiological levels of GH. The recommended dose of GH therapy for children with Prader-Willi syndrome is 0.035 mg/kg/day.

According to the FDA-approved labeling, GH should only be used in the long-term treatment of pediatric patients with genetically confirmed Prader-Willi syndrome when the diagnosis includes GH deficiency. The FDA has received reports of fatalities after the initiation of somatropin therapy in pediatric patients with Prader-Willi syndrome and having one or more risk factors, including severe obesity, history of upper airway obstruction or sleep apnea, and unidentified respiratory infection. Male sex may confer added risk to those with one or more of these risk factors. The FDA-approved labeling of Humatrope (Eli Lilly Co.) was revised to state that GH is contraindicated in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment. The FDA recommends that patients with Prader-Willi syndrome be evaluated for signs of upper airway obstruction and sleep apnea prior to therapy initiation. Treatment should be interrupted in patients showing signs of upper airway obstruction (including onset of increased snoring) and/or sleep apnea. All patients with Prader-Willi syndrome being treated with GH should be managed effectively for weight control and monitored for signs of respiratory infection. The FDA emphasizes the need for early diagnosis and aggressive treatment of these infections.

Chronic renal insufficiency (CRI): Growth delay in children with CRI may result from numerous physiologic derangements, including acidosis, secondary hyperparathyroidism, malnutrition, or zinc deficiency. Before initiation of GH treatment in patients with CRI, existing metabolic derangements (such as acidosis, secondary hyperparathyroidism, and malnutrition) should be corrected. Growth failure in children with chronic renal insufficiency is thought to be due to be multifactorial, with one of the factors being reduced sensitivity to GH rather than GH insufficiency. The dose of growth hormone generally recommended for children with chronic renal insufficiency (0.045-0.050 mg/kg/day) is higher than that for children with classic GH deficiency.

Children born small for gestational age (SGA) : In July 2001, Genotropin received approval as an orphan by the FDA for "long-term treatment of growth failure in children who were born small for gestational age (SGA) who fail to manifest catch-up growth by age 2." Studies that were presented to the FDA and published controlled clinical trials have been relatively short term (2 to 6 years) and show, as would be expected, some normalization ("catch up") of growth of children born small for gestational age. Short term clinical studies have shown that, while growth hormone administration induces catch-up growth in SGA children, it also increases skeletal maturation, so that little or no gain in final adult height would be expected (Stanhope, et al., 1991; Zeghir, et al., 1996; Coutant, et al., 1998; Vance & Mauras, 1999).

The first randomized controlled clinical trial of GH treatment for SGA children reporting on final adult height showed that GH supplementation had induced catch-up growth, but a relatively small increase in final adult height that was less than the child’s genetic potential. Carel, et al. (2003) reported on a study of 168 short children born SGA who were randomized to receive either growth hormone supplementation until attainment of adult height or no treatment. The investigators report that this study differs from previous published studies of GH therapy for SGA children in that this is the first published randomized controlled clinical study that reports on final adult heights. In addition, this study differs from previous studies in that SGA children with GH deficiency were excluded.

The investigators reported that the adult heights of GH-treated SGA patients were greater than those of control patients, with a difference of 0.6 standard deviation score (SDS) units (95% confidence interval (CI), 0.2-0.9) between groups (Carel, et al., 2003). Although the gain in height statistically significant, it is small and treated SGA children remain relatively short compared to peers of normal stature. In this study, the difference observed between treated and control children was 2.7 cm [1.06 inches] in boys and 4.2 cm [1.65 inches] in girls.

The observed effect of growth hormone supplementation on final adult height in patients born small for gestational age was no greater than the reported effect growth hormone supplementation on the final adult height of patients with idiopathic short stature (Carel, et al., 2003). The investigators summarize published studies of growth hormone supplementation in children with idiopathic short stature that show differences in adult height between treated and untreated children ranging from 0.6 SDS to 1.3 SDS.

SGA children in this study initiated growth hormone treatment at a mean age of 10.5 years in girls and 12.5 years in boys, and the duration of treatment varied between 6 months and 3.5 years (Carel, et al., 2003). The investigators reported that although the treatment duration was shorter than in other studies of growth hormone supplementation for SGA children, the dose of GH supplementation was about 50% higher than used in most other studies, the effects of GH supplementation tend to decrease with duration of therapy, and the overall results were similar to other studies of GH supplementation of SGA children. The investigators concluded that although growth hormone supplementation increases final adult height in SGA children, the children remain short relative to their peers, and the clinical significance of this relatively small increase in height in improving the child’s functional capacity, self perception and self-esteem is unclear.

In addition, the long-term effects of growth hormone supplementation children born small of gestational age are unknown. Root (2002) explained that children born small for gestational age are at greatly increased risk for the development of insulin resistance and hyperinsulinism, which is associated with the “metabolic syndrome” of impaired carbohydrate tolerance progressing to type 2 diabetes mellitus, dyslipidemia, hypertension, increased mortality due to coronary artery disease, and in female hyperandrogenism and the polycystic ovarian syndrome. Growth hormone administration is also associated with insulin resistance and hyperinsulinism in IUGR children and other subjects, although these effects may be reversible. “Interestingly, the development of type 2 diabetes mellitus is not only related to subnormal fetal growth but also to increased rates of linear growth between 7 and 15 years of age. It is precisely at this age that [growth hormone] is to be administered to subjects with IUGR to increase the rate of linear growth, potentially increasing still further their risk for development of type 2 diabetes mellitus.”

In an editorial, Silverstein and Shulman (2003) explained:

“The use of [growth hormone] has only recently been approved for use in SGA children with short stature and normal growth hormone responses; hence, its use will likely increase in this population. Its effect on long-term insulin sensitivity in an already at-risk population and later development of type 2 diabetes is not yet known. In a study of more than 23,000 children registered in a pharmaco-epidemiological survey of GH-treated patients, Cutfield, et al. (2000) found an increase in type 2 diabetes (using American Diabetes Association criteria) 6-fold greater than expected for the background populations. This risk may be even greater, more than 20-fold, when ethnically similar populations are used for comparison, and the less stringent World Health Organization criteria for abnormality are applied. These observations are cautionary in light of the now well-established risk of adult type 2 diabetes in low-birth-weight-for-age. Several studies have demonstrated an increased risk of insulin resistance and type 2 diabetes in adults who were small at birth. One study of 23,000 healthy U.S. men found a 2-fold increased risk of type 2 diabetes if they were SGA.”

The authors concluded that "[l]onger-term studies comparing the risk of type 2 DM and associated co-morbidities in rhGH-treated SGA children to untreated SGA children will be needed" and "[o]nly with extended follow-up can we be assured that the structural benefits outweigh the possible long-term risks."

Stanhope (2000) commented on the use of growth hormone in children born small for gestational age and intrauterine growth retardation (IUGR) children:

More than any other condition associated with short stature and treated with GH particular caution should be applied to the long-term sequelae of children with IUGR. There is now convincing evidence that IUGR is a predisposing factor to the development of hypertension, diabetes and cardiovascular disease in adult life. As the dose of administered GH needs to be pharmacological, and in the order of two or three times replacement dose, long-term follow-up of such treated children into old age will be required for absolute reassurance that high dose GH treatment throughout childhood and adolescence is safe.

Rapaport (2002) has noted, however, that the concern about insulin resistance has been shown not to result in abnormal glucose level or diabetes after as long as 6 years of treatment. Rapaport (2002) cited the results of a study that showed that insulin sensitivity parameters adversely affected during treatment with growth hormone revert to normal within 3 months of treatment. Rapaport also noted that growth hormone treatment of up to 6 years has not been shown to increase lipid levels or substantially increase blood pressure.

Root (2002) noted that the benefits of growth hormone supplementation on the psychological well-being of person’s growth small for gestational age are unknown. “There are as yet no data demonstrating any beneficial effect of treatment on their psychological well-being, educational advancement, or vocational attainment” (Root, 2002).

According to the FDA-approved labeling for Genotropin brand of growth hormone, the recommended dose of growth hormone for SGA patients is 0.48mg/kg body weight per week (Pharmacia, 2003). Van Pareren, et al. (2003), however, reported on the results of a randomized controlled dose-ranging study of growth hormone in SGA children, and found no significant differences in outcomes of adult height SDS or gain in height between patients assigned to GH at the recommended dose of 0.48 mg/kg per week and patients assigned to GH therapy at half the usual recommended dose or 0.24 mg/kg per week.

Experimental and Investigational Indications :

HIV lipodystrophy syndrome:
Aetna considers GH treatment for HIV patients with lipodystrophy syndrome to be experimental and investigational. Even though preliminary observations suggest that recombinant human GH may lead to partial regression of fatty Buffalo humps and to a decrease in waist size secondary to truncal obesity, there is no definitive evidence of effectiveness of growth hormone for this indication.

Constitutional delay in growth and development:
Constitutional delay of growth is characterized by normal prenatal growth followed by growth deceleration during infancy and childhood, which is reflected by declining height percentiles at this time. Children with constitutional delay have later timing of puberty than do their peers, allowing a longer period during which they are able to grow. Most commonly, these patients achieve normal adult height if no treatment is given. Although constitutional delay may be treated with GH, other effective and less costly treatments are available. In male patients, the literature shows testosterone or anabolic steroids are effective, and in female patients, low dose estrogens may be used.

Skeletal dysplasias:
GH has been tried in several skeletal dysplasias associated with short stature, most notably achondroplasia. Although GH treatment of patients with achondroplasia has induced some growth acceleration, the literature shows the growth velocities achieved have been insufficient to produce catch-up growth. Thus, the height of these patients is not sufficiently altered so that it can approach the normal range for height.

Kyphomelic dysplasia is a bone dysplasia with severe rhizomelic limb shortening, bowed extremities and dimples over the bowing. Other reported features include truncal shortening, short stature, and micrognathia. Intelligence is normal. There is spontaneous improvement of the bowing with growth. There is a lack of evidence on the use of GH in kyphomelic dysplasia.

Osteogenesis imperfecta:
Osteogenesis imperfecta is caused by mutations in the gene for type I collagen. It is associated with bone demineralization and, in many instances, with retarded bone growth. GH has not been proven to be consistently effective in improving bone growth and mineralization in patients with this condition.

Down syndrome and other syndromes associated with short stature and malignant diathesis:
Because short stature is characteristic of many syndromes, GH therapy has been attempted in several conditions, including Down syndrome, Fanconi syndrome, and Bloom syndrome. The high basal risk of malignant tumor or leukemia in these syndromes, however, has led many pediatric endocrinologists to recommend against the use of GH because the potential for GH to increase the risk of malignancy.

Treatment of acute catabolism:
GH is not recommended for treatment of acute catabolism, including preoperative and postoperative treatment, critically ill patients, and burn patients. The results of two clinical trials of GH therapy for critically ill patients showed a significantly higher mortality in GH-treated patients.

Intrauterine growth retardation and Russell Silver syndrome:
Children with a history of intrauterine growth retardation (IUGR) are more likely to have subnormal growth. Silver-Russell syndrome is a disorder characterized by IUGR and feeding difficulties and dysmorphic features such as limb asymmetry, triangular face, and deflection of one or more fingers (clinodactyly). Clinical studies have examined the potential for growth hormone to improve outcomes in infants with intrauterine growth retardation and Russell Silver syndrome. In these studies, GH treatment was found to have no significant impact on growth, body composition, net protein gain and glucose metabolism. These results may be explained by a relative GH insensitivity or resistance during this period of early preterm life.

Miscellaneous conditions in children:
Short-term acceleration of growth as a result of growth hormone therapy has also been reported in children with Noonan's syndrome, spinal cord defects, hypophosphatemic rickets, and cystic fibrosis; some of these children had impaired growth hormone production. However, no studies have prospectively assessed linear growth until achievement of final height. Current guidelines do not recommend growth hormone for children with these conditions.

Chronic fatigue syndrome:
A systematic evidence review of interventions for chronic fatigue syndrome prepared by the UK National Health Service Centre for Reviews and Dissemination (2002) identified one small clinical trial of GH for chronic fatigue syndrome (Moorkens, et al., 1998), and found that "no conclusions regarding the effect of [growth hormone] treatment can be drawn from this trial.” An assessment prepared for the Agency for Healthcare Quality and Research also concluded that there is insufficient evidence of the effectiveness of GH as a treatment for chronic fatigue syndrome (Mulrow, et al., 2001).

Miscellaneous conditions in adults:
Limited data are available on the effectiveness of GH in an array of conditions in adult patients, including chronic catabolic states, older men and women, postoperative patients, those with states associated with excessive glucocorticoids, obese/morbid obese patients, osteoporosis, muscular dystrophy, and those with infertility, but no consistent benefit has been shown. Until more data are available, however, guidelines do not recommend long-term GH therapy in these conditions.

Short stature associated with Crohn’s disease:
Growth failure often complicates Crohn's disease in childhood. Abnormalities in the GH/insulin-like growth factor-1 axis may occur. In a randomized controlled study, Calenda et al (2005) examined the effects of administered GH on growth in these patients. A total of 7 children (6 boys and 1 girl; age of 11.9 to 16 years) with Crohn's disease and growth failure were enrolled. In phase 1, patients were randomized to either GH (0.05 mg/kg per day) or placebo; in phase 2, patients who received placebo during the first year received GH for various time periods. Follow-up was every 3 months for up to 2 years. During placebo treatment (4 patients), mean height-for-age z score (haz) increased 0.23 in the first half year and 0.55 in the second half year. The mean improvement in haz during the first half year of GH treatment (7 patients) was 0.13; during the second half year (5 patients), haz decreased 0.01. Effects of GH varied among patients; 2 patients grew only when nutritional supplementation was added. Observed changes were not statistically significant. Serum insulin-like growth factor-1 levels correlated with height velocity. Only 2 patients later reached expected adult height. These investigators concluded that GH treatment at the dose given did not stimulate growth in children with Crohn's disease and short stature. Whether or not GH plus nutritional therapy would be effective in promoting sustained catch-up growth remains to be determined.

Other Indications for Growth Hormone:

Idiopathic short stature:
Aetna benefit plans cover treatment of disease or injury; Aetna does not consider idiopathic short stature a disease. A heterogeneous group of otherwise apparently normal children who are two or more standard deviations below the mean for height, but who have normal serum growth hormone responses to stimuli are classified as having genetic short stature, normal-variant familial short stature if their parents are short, constitutional delay of growth if there is a delay in skeletal maturation, or idiopathic short stature. Treatment of these children with growth hormone is controversial with regard to both efficacy and ethics. Although GH therapy initially causes growth acceleration, it also accelerates pubertal development and advances bone age so that the duration of growth during puberty is shortened.

One randomized controlled clinical trial (RCT) reported near final height (NFH) in of girls with idiopathic short stature. Two published studies reporting final height were prospective non-randomised controlled trials, one in peripubertal boys with subnormal integrated GH concentration and one in short, normal children. Results from the RCT including NFH found that treated girls were approximately 7.5 cm taller than randomised control girls and 6 cm taller than girls who refused consent. Other long term studies also suggest that final height is increased by GH treatment. However, the increase is between 2 cm to 7 cm, and treated individuals remain relatively short when compared with peers of normal stature.

Short stature does not result in disease or functional limitation. Therefore, the use of growth hormone for this condition considered an enhancement of human performance or appearance rather than as a medically necessary treatment of disease. All normal and healthy populations have genetic variation that will give rise to individuals with short stature. In a position statement, the American Academy of Pediatrics (1997) has noted that, by definition, children with short stature relative to their peers will always exist and targeting the current cohort for medical intervention will merely replace them with another cohort.

Studies have demonstrated that the use of growth hormone in children with ISS increases growth rate and height and may minimally increase final height, as compared with baseline predicted values, but generally does not increase final height to normal levels. Some argue, however, that the major criterion for the use of GH in ISS should be improvement in the individual patient's quality of life, regardless of whether final height is improved or not. But, whether short stature itself (with no pathological basis) correlates with psychosocial dysfunction of any kind is debated. An assessment conducted by NICE stated that “Most studies concur that shortness alone does not necessarily result in negative psychological consequences. Many studies have found no relation between degree of shortness and psychological problems.”

In addition, there is no adequate evidence from randomized prospective clinical studies demonstrating clinically significant improvements in functional status or reductions in psychological dysfunction in children with idiopathic short stature who are treated with growth hormone. In addition, some experts maintain, however, that psychological dysfunction may be better addressed by psychological intervention and counseling than by the use of growth hormone.

In a position statement on the use of growth hormone in children, the American Academy of Pediatrics (1997) has stated:

“In many other instances, the use of GH has been justified on the grounds that persons with short stature (defined as more than 2 SDs below the mean for age and sex) experience stigma in an affluent society. These children are often teased in school about their short stature; moreover, empiric evidence indicates that numerous social benefits are linked to tall stature. In some children, short stature may be part of an acquired or inherited disorder. For these children, growth augmentation is viewed as an avenue to normalcy. Despite these concerns and the fairly extensive use of recombinant human GH in these patient groups, no objective current data demonstrate the psychosocial benefits of hormonal therapy in this group of children and few physiologic data demonstrate an effect on final adult height. The above considerations have led some to question whether research on the use of human GH to attempt to increase the final adult height of non-GH-deficient children is warranted.”

“It is also unclear whether GH therapy reduces the psychosocial problems that very short children may experience. Indeed, there is evidence that GH therapy exacerbates these problems in some children owing to unrealistic expectations concerning the therapeutic outcome and enhanced feelings that something is ‘wrong’ with them.“

“There is also the question of how to define treatment ‘success.’ Short stature is a characteristic that must be defined relative to the general population in which people will always be of different heights. Thus, even if GH therapy were available to and effective in all ‘short’ stature children, a population of short children will still exist; they will simply be a few inches taller than those in the former population. “

Root (2002) stated that “[m]any studies document the psychological good health and normal educational progress of healthy children with idiopathic short stature. In fact, short children with behavioral problems and learning disabilities are referred more frequently for endocrine evaluation than are their normally achieving age and height peers. Furthermore, it is quite possible that the extensive testing, daily injections, and frequent medical visits needed during [growth hormone] administration may imprint upon the child (and reinforce to the parent) a negative concept of his/her self worth.”

There is no adequate evidence that short stature, in and of itself, is associated with functional limitations. A systematic evidence review prepared for the Agency for Healthcare Research and Quality evaluated the relationship of short stature in childhood with functional limitations, including intelligence, academic achievement, behavior, visual-motor perception, and psychomotor development (Wheeler, et al., 2003). The assessment concluded that there was no evidence that short stature in children is associated with severe functional limitations.

Pegvisomant (Somavert) for Acromegaly :

Acromegaly is a potentially life-threatening disease triggered by an excess of GH. Symptoms include headaches, profuse sweating, swelling, joint disorders, changes in facial features, as well as enlarged hands, feet and jaw. If untreated, patients with acromegaly often have a shortened life-span because of heart and respiratory diseases, diabetes mellitus and cancer.

In 2003, the FDA approved pegvisomant (Somavert) for the treatment of acromegaly in patients who have had an inadequate response to existing therapies. Pegvisomant, a polyethylene glycol derivative of human GH, is the first in a new class of drugs called GH receptor antagonists. It competes with endogenous GH for the receptor and results in suppression of serum insulin-like growth factor (IGF-1). Clinical studies have shown that pegvisomant normalized concentrations of IGF-I in more than 90 % of patients by blocking the effects of GH. The most commonly reported adverse effects with pegvisomant were injection site reactions, sweating, headache and fatigue.

CPT Codes
CPT Codes covered if selection criteria is met :
90772	Therapeutic, prophylactic or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
90782	Therapeutic, prophylactic or diagnostic injection (specify material injected); subcutaneous or intramuscular (deleted 12-31-05)

Other CPT Codes related to the CPB :
70450 - 70470	Computed tomography, head or brain; without contrast material, with contrast material(s), or without contrast material, followed by contrast material(s) and further sections
70496	Computed tomography angiography, head, without contrast material(s), followed by contrast material(s) and further sections, including image post-processing
70551 - 70553	Magnetic resonance (e.g., proton) imaging, brain (including brain stem); without contrast material, with contrast material(s), or without contrast material, followed by contrast material(s) and further sequences
80418	Combined rapid anterior pituitary evaluation panel
80422	Glucagon tolerance panel; for insulinoma
80428 - 80430	Growth hormone stimulation panel (e.g., arginine infusion, l-dopa administration) or growth hormone suppression panel (glucose administration)
80434	Insulin tolerance panel; for ACTH insufficiency
80435	for growth hormone deficiency
83003	Growth hormone, human (HGH) (somatotropin)
84305	Somatomedin
84436	Thyroxine; total
86277	Growth hormone, human (HGH), antibody
88271 - 88275	Molecular cytogenetics
88280 - 88289	Chromosome analysis
88291	Cytogenetics and molecular cytogenetics; interpretation and report
99601 - 99602	Home infusion/specialty drug administration

HCPCS Codes
HCPCS Codes covered if selection criteria are met :
J2940	Injection, somatrem, 1 mg
J2941	Injection, somatropin, 1 mg
Q0515	Injection, semorelin acetate, 1 mcg
Q2014	Injection, semorelin acetate, 0.5 mg (deleted 12-31-05)
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

Other HCPCS Codes related to the CPB :
B4164 - B5200	Parenteral nutrition solutions and supplies
B9004 - B9006	Parenteral nutrition infusion pump
S9364 - S9368	Home infusion therapy, total parenteral nutrition (TPN)

ICD-9 Codes
ICD-9 Codes covered if selection criteria are met :
042	Human immunodeficiency virus (HIV) disease
191.0 - 191.9	Malignant neoplasm of brain
194.3	Malignant neoplasm of pituitary gland and craniopharyngeal duct
198.3	Secondary malignant neoplasm of brain and spinal cord
225.0	Benign neoplasm of brain
227.3	Benign neoplasm of pituitary gland and craniopharyngeal duct (pouch)
235.7	Neoplasm of uncertain behavior of trachea, bronchus, and lung
237.0	Neoplasm of uncertain behavior of pituitary land and craniopharyngeal duct
239.6	Neoplasm of unspecified nature of brain
253.0	Acromegaly and gigantism
253.2	Panhypopituitarism
253.3	Pituitary dwarfism (e.g., isolated deficiency of [human] growth hormone)
253.7	Iatrogenic pituitary disorders
579.3	Other and unspecified postsurgical nonabsorption
588.0	Renal osteodystrophy
758.6	Gonadal dysgenesis
759.2	Anomalies of other endocrine glands
759.81	Prader-Willi syndrome
783.43	Short stature
783.7	Adult failure to thrive
799.4	Cachexia
990	Effects of irradiation, unspecified
V15.3	Personal history of irradiation
E932.0	Adrenal cortical steroids causing adverse effects in therapeutic use

ICD-9 Codes not covered for indications listed in the CPB :
250.50 - 250.53	Diabetes with ophthalmic manifestations
253.4	Other anterior pituitary disorders
253.8	Other disorders of the pituitary and other syndromes of diencephalohypophyseal origin
259.1	Precocious puberty
270.0	Disturbances of amino-acid transport
277.00 - 277.09	Cystic fibrosis
278.00 - 278.02	Overweight and obesity
296.00 - 296.99	Affective psychoses
298.0	Depressive type psychosis
300.4	Neurotic depression
308.3	Other acute reactions to stress
309.81	Prolonged post-traumatic stress disorder
311	Depressive disorder, not elsewhere classified
348.2	Benign intracranial hypertension
359.0 - 359.9	Muscular dystrophies and other myopathies
362.01 - 362.07	Diabetic retinopathy
401.0 - 405.99	Hypertensive disease
518.81	Acute respiratory failure
518.83	Chronic respiratory failure
518.84	Acute and chronic respiratory failure
555.0 - 558.9	Noninfectious enteritis and colitis
606.0 - 606.9	Infertility, male
628.0 - 628.9	Infertility, female
714.30 - 714.33	Juvenile chronic polyarthritis
733.00 - 733.09	Osteoporosis
741.00 - 741.93	Spina bifida
743.57	Specified anomalies of optic disc
756.4	Chondrodystrophy
756.51	Osteogenesis imperfecta
758.0	Down’s syndrome
759.89	Other specified congenital anomalies
764.20 - 764.9	Fetal malnutrition without mention of "light for dates" and fetal growth retardation, unspecified
780.71	Chronic fatigue syndrome
940.0 - 949.5	Burns
V22.2	Pregnant state, incidental
V24.1	Lactating mother

Other ICD-9 Codes related to the CPB :
251.2	Hypoglycemia, unspecified
752.64	Micropenis
764.00 - 764.19	"Light-for-dates" without mention of fetal malnutrition or with fetal malnutrition
V21.30 - V21.35	Low birth weight status
V42.0	Kidney transplant
V45.1	Renal dialysis status

Revision Dates

Original policy: August 14, 1997
Revised: July 7, 1998; October 28, 1998; December 1, 1998; March 2, 1999; June 23, 1999; September 30, 1999; November 22, 1999; February 5, 2002; March 15, 2002; April 26, 2002; September 24, 2002; September 23, 2003; May 11, 2004; September 14, 2004; October 26, 2004; April 12, 2005; July 19, 2005; April 18, 2006

The above policy is based on the following references:

United States Pharmacopeial Convention, Inc (USPC). USP Dispensing Information. Volume I -- Drug Information for the Health Care Professional. Rockville, MD: USPC; 1998.
American Society of Health-System Pharmacists, Inc. American Hospital Formulary Service Drug Information 98. Bethesda, MD: American Society of Health-System Pharmacists; 1998.
No authors listed. 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;99(1):122-129.
Ghigo E, Bellone J, Aimaretti G, et al. Reliability of provocative tests to assess growth hormone secretory status. Study in 472 normally growing children. J Clin Endo Metab. 1996;81:3323-3327.
Rose SR, Minicchi G, Barnes KM, et al. Overnight growth hormone concentrations are usually normal in pubertal children with idiopathic short stature - A clinical research center study. J Clin Endo Metab. 1996;81:1063-1068.
Donaldson MDC. Jury still out on growth hormone for normal short stature and Turner’s syndrome. Lancet. 1996;348:3-4.
Hindmarsh PC, Brook CGD. Final height of short normal children treated with growth hormone. Lancet. 1996;348:13-16.
Hindmarsh PC, Brook CGD. Short stature and growth hormone deficiency. Clin Endocrinol. 1995;43:133-142.
Rosenfeld RG, Albertsson-Wilkand K, Frasier SD. Diagnostic controversy: The diagnosis of childhood growth hormone deficiency revisited. J Clin Endo Metab. 1995;80:1532-1540.
No authors listed. Guidelines for the use of growth hormone in children with short stature. A report by the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. J Pediatr. 1995;127(6):857-867.
Oregon Health and Science University (OHSU), Department of Pathology, Director of Clinical Laboratory Services. OHSU Laboratory Services Manual. Portland, OR: OHSU; 2003. Available at: http://www.ohsu.edu/pathology/wardman/frame.htm. Accessed August 26, 2003.
Barker AN, ed. LabPLUS Electronic Handbook. Auckland District Health Board. Auckland, NZ: LabPLUS; July 16, 2003. Available at: http://www.adhb.govt.nz/LabPlusHandbook/. Accessed August 26, 2003.
Allen DB, Brook CGD, Bridges NA, et al. Therapeutic controversies: Growth hormone treatment of non-GH deficient subjects. J Clin Endo Metab. 1994;79:1239-1247.
McKenna SP, Doward LC, Alonso J, et al. The QoL-AGHDA: An instrument for the assessment of quality of life in adults with growth hormone deficiency. Qual Life Res. 1999;8(4):373-383.
Smith WT, Nam TJ, Underwood LE, et al. Use of insulin like growth factor binding protein-2, IGFBP-3 and IGF-1 for assessment growth hormone status in short children. J Clin Endocrin Metab. 1993;77:1294-1299.
Hopwood NJ, Hintz RL, Gertner JM, et al. Growth hormone response of children with non growth hormone deficiency and marked short stature during three years of growth hormone therapy. J Pediatr. 1993;123:215-222.
Eiholzer U, Gisin R, Weinmann C, et al. Treatment with human growth hormone in patients with Prader-Labhart-Willi syndrome reduces body fat and increases muscle mass and physical performance. Eur J Pediatr. 1998;157(5):368-377.
Lindgren AC, Hagenas L, Muller J, 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 Paediatr Suppl. 1997;423:60-62.
Carr A, Samaras K, Chisholm DJ, et al. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet. 1998;351(9119):1881-1883
Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidemia, and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998;12:F51-F58.
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Torres R, Unger KW. Treatment of dorsocervical fat pads ( Buffalo hump) and truncal adiposity with Serostim (recombinant human growth hormone) in patients with AIDS maintained on HAART [Abstract 32164]. 12th World AIDS Conference, Geneva, Switzerland, 1998.
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Appendix

Growth Charts : Growth charts for infants, children and adolescents are posted at the following internet sites: National Center for Health Statistics: http://www.cdc.gov/nchs/about/major/nhanes/growthcharts/clinical_charts.htm. Eli Lilly Pharmaceuticals: http://www.humatrope.com/professionals/humatrope.jsp?reqNavId=4.2..2 (this table includes growth charts with curves down to 3 standard deviations). Height Velocity Tables : Figure 1: Height Velocity (cm/year) - Girls

Age	3 rd Percentile	10 th Percentile	25 th Percentile
2.0	6.4	7.1	8.4
2.5	5.8	6.7	7.7
3.0	5.5	6.3	7.2
3.5	5.2	6.0	6.7
4.0	5.0	5.8	6.4
4.5	4.8	5.4	6.2
5.0	4.6	5.2	5.9
5.5	4.5	5.0	5.7
6.0	4.4	5.0	5.6
6.5	4.3	4.9	5.5
7.0	4.3	4.8	5.4
7.5	4.3	4.8	5.3
8.0	4.2	4.7	5.2
8.5	4.1	4.7	5.2
9.0	4.1	4.8	5.2
9.5	4.2	4.9	5.3
10.0	4.4	5.0	5.6
10.5	4.8	4.6	6.1
11.0	5.8	6.4	7.0
11.5	6.1	6.9	7.5
12.0	5.2	6.3	6.8
12.5	3.5	4.6	5.5
13.0	2.4	3.0	3.7
13.5	1.3	1.7	2.4
14.0	0.3	0.8	1.4
14.5	0	0.2	0.5

Figure 2: Height Velocity (cm/year) - Boys

Age	3 rd Percentile	10 th Percentile	25 th Percentile
2.0	6.3	6.7	8.0
2.5	5.7	6.4	7.4
3.0	5.4	6.1	7.0
3.5	5.1	5.8	6.6
4.0	4.9	5.7	6.3
4.5	4.8	5.5	6.1
5.0	4.6	5.3	5.9
5.5	4.4	5.1	5.7
6.0	4.3	5.0	5.7
6.5	4.2	4.9	5.4
7.0	4.1	4.7	5.3
7.5	4.0	4.6	5.2
8.0	3.8	4.5	5.0
8.5	3.8	4.4	4.9
9.0	3.8	4.4	4.8
9.5	3.8	4.3	4.7
10.0	3.7	4.2	4.7
10.5	3.7	4.2	4.6
11.0	3.7	4.2	4.6
11.5	3.8	4.2	4.8
12.0	4.0	4.7	5.1
12.5	4.9	5.5	6.2
13.0	6.1	7.3	8.0
13.5	7.1	8.0	8.7
14.0	6.0	7.2	7.5
14.5	4.3	5.1	5.6
15.0	2.3	3.5	4.0
15.5	1.1	2.2	2.6
16.0	0.3	1.2	1.6
16.5	0.0	0.5	1.0
17.0	0.0	0.1	0.5

Source: Interpolated from data from Tanner & Davies (1995). Conversion Factor: 1 centimeter (cm) = 0.394 inches (in). 1 in = 2.54 cm. Insulin-like Growth Factor I (IGF-1) ELISA : Figure 3: IGF-1 Values 2 Standard Deviation Scores Below the Mean for Age: It is recommended that the laboratory’s own reference ranges be used in determining whether the patient’s IGF-1 value is abnormal (falling two or more standard deviations below the mean for age and sex). If the laboratory’s own reference range is not available, the following may be used as a guide to IGF-1 values falling two or more standard deviations below the mean:

Age (years)	Males (ng/mL)	Females (ng/mL)
0-5	17	17
6-8	88	88
9-11	110	117
12-15	202	261

Policy Statements

Growth Hormone (GH), Growth Hormone Releasing Hormone (GHRH), and Growth Hormone Antagonists (Revised)

Policy

Background

CPT Codes

HCPCS Codes

ICD-9 Codes

Appendix