This document addresses the use of human growth hormone for the treatment of children, adolescents and adults with a variety of medical conditions.

Note: According to U.S. Federal Food, Drug and Cosmetic Act, Sec. 301. [21 U.S.C. §303(e)], Growth Hormone may not be legally prescribed for any condition not approved by the U.S. Food and Drug Administration.*

* http://www.fda.gov/opacom/laws/fdcact/fdcact3.htm

Medically Necessary: In this document, procedures or drug therapies are considered medically necessary if there is a significant physical functional impairment AND the procedure can be reasonably expected to improve the physical functional impairment.

Reconstructive: In this document, procedures or drug therapies are considered reconstructive when intended to address a significant variation from normal, related to accidental injury, disease, trauma, treatment of a disease or congenital defect.  Note:  Not all benefit contracts include benefits for reconstructive services as defined by this document. Benefit language supersedes this document.

GROWTH HORMONE THERAPY IN CHILDREN AND ADOLESCENTS:

A.        Medically Necessary

Growth hormone replacement therapy is considered medically necessary for children with growth hormone deficiency (GHD) as documented by any one of the following:

1. A subnormal response (less than 10 ng/ml) to any TWO of the following standard growth hormone (GH) stimulation tests: 
   • Arginine;
   • Clonidine;
   • Glucagon;
   • Insulin induced hypoglycemia;
   • L-dopa - Propranolol; or
2. Documented presence of at least two other pituitary hormone deficiencies, in addition to IGF-1 measurement below age-appropriate level; or
3. Neonates with hypoglycemia and clinical and hormone evidence of hypopituitarism (at least one GH stimulation test is subnormal).

 B.       Reconstructive

Growth hormone therapy is considered reconstructive in nature for individuals who do not have GHD, but who meet both (1 and 2) of the following criteria:

1. The child meets any of the following:
   • The child's height is at least 2.25 but less than 2.5 standard deviations below the mean for his or her age and gender, and growth velocity is less than the 10^th percentile over one year; or
   • The child's height is at least 2.5 standard deviations below the mean for his or her age and gender, regardless of growth velocity; and
2. The child has a condition known to be responsive to growth hormone therapy, including, but not limited to:
   • Chronic renal insufficiency; or
   • Idiopathic short stature; or
   • Children with Prader-Willi syndrome, who are not severely obese (BMI less than 35), and who do not meet the medically necessary criteria described above; or
   • Noonan syndrome; or
   • Turner syndrome; or
   • Children with Short Stature Homeobox (SHOX) gene; or
   • Children born small for gestational age defined as all of the following:
     • Child was born small for gestational age (SGA), defined as birth weight or length 2 or more standard deviations below the mean for gestational age (infants with intrauterine growth restriction or Russell-Silver Syndrome resulting in SGA are included in this category); and
     • Child fails to manifest catch up growth before 4 years of age, defined as height 2 or more standard deviations below the mean for age and sex; and
     • Other causes for short stature such as growth inhibiting medication, chronic disease, endocrine disorders, and emotional deprivation or syndromes (except for Russell-Silver syndrome) have been ruled out.

C.        Continuation of Therapy 

Continuation of growth hormone therapy is appropriate for children who previously met criteria for medically necessary or reconstructive treatment when they meet the following criteria (i.e., either medically necessary or reconstructive), and, if reconstructive, have not met the requirements for termination of GH therapy described in Section D below: 

• Review of the medically necessary or reconstructive nature of GH therapy for treatment of growth failure in children should occur on an annual basis for all conditions; and
• A doubling of pre-treatment growth rate or an increase in pre-treatment growth rate of 3 cm/year or more seen in the first year of therapy; and
• For therapy continuing past the first year, growth rate remains above 2.5 cm/year (does not apply to children with prior documented hypopituitarism); and
• For children over age 12, either of the following:
  • An X-ray report with evidence that epiphyses have not yet closed (does not apply to children with prior documented hypopituitarism); or
  • A Sexual Maturity Rating (SMR, Tanner Stage) less than or equal to 3.

D.       Termination of Therapy for Reconstructive Indications 

Growth hormone therapy is considered no longer reconstructive when any of the following criteria are met:

• Bone age = 16 years (male), or = 14 years (female) is reached, or
• Epiphyseal fusion has occurred, or
• "Mid-parental height" is achieved. Mid-parental height = (father's height + mother's height) divided by 2, plus 2.5 inches (male) or minus 2.5 inches (female).

E.        Transitioning Adolescents with Childhood Onset GH Deficiency to Treatment in Adulthood

Growth hormone therapy is considered medically necessary for the treatment of adolescents and young adults with childhood onset GHD, who have completed linear growth as defined by growth rate less than 2 cm per year and either of the following sets of criteria (#1 or #2 below) are met:

1. GH treatment has been stopped for at least one (1) month; and the diagnosis of GHD has been reconfirmed as follows:
   • For individuals with idiopathic isolated GHD: A documented subnormal response* to two standard growth hormone stimulation tests, or subnormal response to one provocative test and low IGF-I/IGFBP-3; or
   • For individuals with multiple pituitary hormone deficiencies with or without tumor/radiation, a documented subnormal response* to one provocative GH test or low IGF-I/IGFBP-3; or
     *Subnormal response is defined as serum GH concentration of less than 10 ng/ml.  Acceptable stimulation tests include: insulin induced hypoglycemia, arginine, glucagon, clonidine, or L-dopa - propranolol.
2. Documented presence of any of the following conditions. (i.e., growth hormone stimulation tests are not required in this subgroup of individuals):
   • A known genetic mutation associated with deficient growth hormone production or secretion; or
   • Hypothalamic-pituitary tumor or structural defect; or
   • At least three (3) other pituitary hormone deficiencies. 

II.        GROWTH HORMONE THERAPY IN ADULTS

Growth hormone therapy is considered medically necessary for the treatment of adult growth hormone deficiency (GHD), also known as somatropin deficiency syndrome, for individuals with any of the following conditions:

1. Documented GHD in childhood; or
2. Documented hypopituitarism as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, trauma, or aneurysmal subarachnoid hemorrhage.

The diagnosis of GHD must be confirmed, or reconfirmed, by any the following:

• A documented subnormal response in adults to two standard growth hormone stimulation tests (Possible stimulation tests include, but are not limited to: insulin-induced hypoglycemia and combined arginine-growth hormone releasing hormone); defined as:
  1. Serum GH concentration of less than or equal to 5 ng/ml when using insulin induced hypoglycemia testing; or
  2. Serum GH concentration of less than or equal to 4.1 ng/ml when using arginine; or
• Subnormal response to one stimulation test for adults with documented hypothalamic or pituitary disease and one or more additional pituitary hormone deficits; or
• Documented presence of at least three other pituitary hormone deficiencies (i.e., growth hormone stimulation tests are not required in this subgroup of individuals.)

For individuals being treated for GHD due to trauma or aneurysmal subarachnoid hemorrhage, GHD must be reconfirmed at 12 months after the event for therapy to continue.  If retesting is not confirmatory for growth hormone deficiency, continued treatment is considered not medically necessary (Note: See confirmatory criteria above). 

III.       TREATMENT OF AIDS WASTING SYNDROME

Growth hormone is considered medically necessary in the treatment of individuals with AIDS wasting syndrome, defined as a greater than 10% of baseline weight loss that cannot be explained by a concurrent illness other than HIV infection.  Treatment is continued until this definition is no longer met.  Individuals treated with GH for AIDS wasting must simultaneously be treated with antiviral therapy.

IV.       SHORT BOWEL SYNDROME

Growth hormone supplementation is considered medically necessary for the treatment of short bowel syndrome in individuals receiving specialized nutritional support in conjunction with optimal management of short bowel syndrome.  Specialized nutritional support may consist of a high-carbohydrate, low-fat diet adjusted for individual requirements.

V.        INVESTIGATIONAL and NOT MEDICALLY NECESSARY:

Use of GH therapy when applicable criteria above have not been met is considered investigational and not medically necessary including, but not limited to, the following:

• After renal transplant
• Anabolic therapy, except for AIDS, provided to counteract acute or chronic catabolic illness (e.g., surgery, trauma, cancer, chronic hemodialysis) producing catabolic (protein wasting) changes in both adults and children
• Anabolic therapy to enhance body mass or strength for professional, recreational or social reasons.
• Constitutional delay of growth and development
• Cystic fibrosis
• Growth hormone treatment in combination with GnRH agonist (Lupron) as a treatment of precocious puberty
• Hypophosphatemic rickets
• Osteogenesis imperfecta
• Osteoporosis
• Short stature associated with growth hormone insensitivity (Laron Syndrome)
• Therapy in older adults with normally occurring decrease in GH, who are not congenitally GH deficient and who have no evidence of organic pituitary disease (this is referred to as age-related GH deficiency).
• Treatment of congestive heart failure (CHF)
• Treatment of individuals with burns
• Treatment of fibromyalgia
• Treatment of glucocorticoid-induced growth failure
• Treatment of HIV lipodystrophy (fat redistribution syndrome), also referred to as altered body habitus (e.g., buffalo hump), associated with antiviral therapy in individuals with HIV-infection
• Treatment of intrauterine growth restriction (IUGR) or Russell-Silver Syndrome that does not result in SGA
• Treatment of obesity
• Other etiologies of short stature where GH has not been shown to be associated with an increase in final height, including but not limited to achondroplasia and other skeletal dysplasias

Diagnostic testing requiring overnight hospitalization for spontaneous growth hormone secretion is considered investigational and not medically necessary in all cases.

Use of animal growth hormones is considered investigational and not medically necessary in all cases.

Concepts of Medically Necessary and Reconstructive Services 

In this document, the medical necessity of growth hormone requires the documented presence of a growth hormone deficiency (GHD).  The medical necessity of treatment is based on the metabolic abnormalities associated with GHD.  For example, hypoglycemia, frequently severe, may be seen in neonates with growth hormone deficiency.  GHD is also associated with a decrease in bone mass, abnormalities in lipid profiles and increases in other cardiac risk factors.  While there is not a strong chain of evidence linking these abnormalities to an increase in adult morbidity and mortality, based either on an increased incidence of fragility fractures or cardiovascular sequelae, GH therapy for those with documented GHD is considered a standard of care by the medical community.   

In children and adolescents, growth hormone is most commonly used to treat short stature that is anticipated to result in an adult height that is out of the range of normal, defined in this document as less than or equal to 2.5 standard deviations (SD) below the mean.  The short stature may be related to a variety of etiologies, some associated with GHD (i.e., idiopathic GHD, Prader-Willi syndrome) and some with normal GH levels (i.e., Turner syndrome, small for gestational age, idiopathic short stature).  However, an increase in final height is the common denominator underlying the rationale for the therapy.  Furthermore, there is no well defined functional impairment associated with short stature, and no target height that can differentiate the presence or absence of a functional impairment.  Therefore, all indications for GH therapy intended to increase the final adult height are considered reconstructive in nature.  However, it should be noted that in those with GHD, GH therapy is simultaneously given to address the associated metabolic abnormalities, and thus in these individuals GH therapy can be considered either medically necessary or reconstructive.  To be considered medically necessary, GH deficiency must be documented by GH stimulation tests, while height criteria are all that is required to be considered reconstructive. 

While not an element of medical necessity, advocates of GH therapy often cite the potential psychosocial impairments associated with short stature.  However there is inadequate data to determine whether height increases in children with extreme short stature are associated with improved psychosocial improvements.  For example, studies have suggested that short stature is only variably related to psychosocial morbidity (Sandberg, 1994).  In 2003, the Agency for Healthcare Research and Quality (AHRQ) published a review of the possible disability associated with short stature (AHRQ, 2003).  Specifically this review researched the question of whether short stature (defined as less than the 5^th percentile [corresponding to 1.65 SD below the mean]) was associated with severe functional limitations according to the definition of disability by the Social Security Administration.  The report reviewed 31 published papers of varying quality and found inadequate evidence of a variety of functional impairments, including academic achievement, intelligence, visual motor skills, psychomotor development and behavior.  In each of these categories, children with short stature either had testing that was not significantly different from the controls or from population mean, or if the testing was significantly poorer it was still for the most part within 1 standard deviation.   

In January 1997, the American Academy of Pediatrics (AAP) published a document that provided the following comment:

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.

Indications for Growth Hormone Therapy
Documented Growth Hormone Deficiency in Children 

In this document, documentation of GHD is not necessary to establish a reconstructive indication for GH therapy; this can be established by the current height and growth velocity alone.  However, provocative testing remains the standard of care in confirmation of a diagnosis of GHD, and is the basis of the medically necessary criteria.  The currently available tests used for this purpose are not very accurate and it has become accepted practice to conduct two tests to assure that the individual for whom the treatment is proposed actually has GHD.  In addition, documentation of GH deficiency is required to establish the medical necessity of GH therapy in children and adolescents who have completed growth and are transitioning to continued GH replacement as adults.  For example, at completion of linear growth, GH treatment should be stopped for at least 3 months and GH status reassessed to determine whether GH deficiency persists.  For example, peak bone mass is generally considered to be reached by approximately 20 years of age.  Since the accumulation of bone mass continues from 1-7 years after the cessation of linear growth, continuation of GH therapy is indicated for adolescents and young adults who remain GH deficient and who have not achieved peak bone mass.

GH Use in Children with Documented Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a chromosomal abnormality characterized by hypotonia, short stature, hypogonadism and behavioral abnormalities.  Many individuals with PWS demonstrate GH deficiency on GH stimulation testing.  GH is FDA approved for individuals with PWS with this deficiency.  One 4 year study by Carrel and others (2002) reported on a population of 46 children with PWS receiving GH therapy for two years and then randomized to receive one of three different GH doses (0.3 mg/m²d, 1.0 mg/m²d, and 1.5 mg/m²d) for another two years.  The study findings indicate that both the 1.0 mg/m²d and 1.5 mg/m²d regimens resulted in decreased fat mass, and increased lean body mass, resting energy expenditure, and growth velocity. Increases in bone mineral density resulted at all doses.  Prior to treatment, all of these individuals were GH deficient by stimulation testing.  Aside from the well-documented increases in growth velocity, other studies have investigated GH therapy for its impact on metabolic, respiratory and developmental processes in the PWS population.  However, interpretation of these results is complicated by the lack of clear delineation as to whether the individuals were tested for GHD by stimulation testing and if this was used in the study design. 

GH Use in Short-Statured Children Without Documented GH Deficiency or Underlying Pathology 

In July 2003, Humatrope received FDA approval for use in non-GHD short stature (defined for this indication as a standard deviation (SD) of -2.25 below the mean).  Recommendation for approval was supported by data indicating a significant increase in final height with GH treatment compared to placebo; average increases ranged from 1.25 to 2.8 inches, depending on the trials, which differed in baseline characteristics, GH dose, administration, and length of treatment.  For example, one randomized phase III trial (GDHC), which treated children with a height SDS of -2.25 or less with GH or placebo for an average of 4.43 years, found a statistically significant GH treatment effect on final height. Only 27% of placebo-treated subjects and 42% of Humatrope-treated subjects completed the study.  An FDA analysis of final height estimated a treatment effect of 1.25 inches (adjusted for baseline predicted height) with a 95% CI of 0.1 to 2.4 inches.  The manufacturer reported an estimate of a 2-inch gain for GH treatment over placebo based on a separate post hoc analysis. Analysis of final height could only be conducted in 46% of 71 subjects, including 8 subjects who discontinued treatment, and may therefore be biased.  Study E001 randomized 3 doses of Humatrope to children with height SDS of -2.0 or less.  Final height was assessed in a long-term extension (mean 6.47 years) of this study for 21% of 239 subjects.  This subgroup achieved a height gain of 2.1 to 2.8 inches over baseline predicted height; the increased effect in this trial compared to GDHC may be due to differences in starting age and Tanner stage, dose, longer follow-up, or a higher frequency of GH administration.  In addition, a recent meta-analysis of 10 controlled and 28 uncontrolled trials estimate a benefit on adult height of 1.6 to 2.4 inches (Finkelstein, 2002).  Functional impairments were not documented at the beginning or end of the study. 

GH Use in Small for Gestational Age Children

In 2001, Genotropin received orphan drug designation from the FDA for treatment of individuals with SGA, defined as birth weight and/or length at least 2 standard deviations (SDs) below the mean for gestational age (<-2 SD).  The mechanism for the poor sustained growth is not clear.  Most of these children have a normal growth hormone response to provocative testing.  Studies have shown, however, that some of these children have abnormally low levels of IGF-1, suggesting an abnormality in the GH receptor.  Another group of children has demonstrated changes consistent with a partial IGF-1 resistance.  The labeled indication states that GH therapy is indicated for children who have persistent short stature (height below -2 SD); are at least 2 to 3 years of age; and are growing at an average or subnormal rate for age, provided that other causes for short stature such as growth inhibiting medication, chronic disease, endocrine disorders, emotional deprivation or syndromes (except for Russell-Silver syndrome) have been ruled out.  Before GH therapy for a short child who was born SGA is considered, it is important to wait until the spontaneous catch-up phase is completed, which usually occurs by the time a child is 2 to 3 years of age.  Some children (e.g., those born very prematurely) may have a longer period of spontaneous catch-up growth. 

The FDA approval was based on 4 randomized, open-label controlled clinical trials (Genotropin package insert).  Subjects were observed for 12 months before being randomized to receive either 0.24 mg/kg/week or 0.48 mg/kg/week GH or no treatment for 24 months.  After 24 months all subjects received GH.  In subjects receiving the higher dosage of 0.48 mg/kg/wk, the subjects' height improved from a baseline of -3.4 standard deviations to -1.7 standard deviations below the mean.  In contrast, in the control group the standard deviation score improved to a lesser degree, from -3.1 to -2.9 standard deviations below the mean.  The issues associated with this indication for GH are similar to those for other short-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 small for gestational age children, 0.48 mg/kg/week, is a supraphysiologic dose.  For example, in subjects with documented GH deficiency, in which the intent is to provide normal physiologic replacement levels of GH, the recommended dosage is only 0.24 mg/kg/week.  There are very minimal data regarding the psychosocial outcomes of short pediatric or adult stature related to intrauterine growth retardation, and how these outcomes may be affected by GH therapy.  As noted above, data are inadequate to document that short-stature youths have either low self-esteem or a higher than average amount of behavioral or emotional problems (Sandberg, 1994; Am Acad Ped, 1997).

For both small for gestational age children and short-stature children, an additional strategy to achieve target adult heights is to combine GH therapy with gonadotropin hormone releasing (GnRH) analogs, which prolong the prepubertal growth period.  The combined therapy is intended to increase the critical pubertal height gain by delaying the fusion of the epiphyseal growth plates, thus prolonging the period during which GH is active.  This therapy has been suggested for children who are considered short when they enter puberty (Saggase, 1995; Pasquino, 2000; Tanaka, 1999). 

Turner Syndrome 

Short stature is almost universal in Turner syndrome.  Poor growth is evident in utero and further deceleration occurs during childhood and at adolescence, although GHD is a component of the syndrome.  The mean adult height for those with Turner syndrome is 58 inches (4 ft 10 inches).  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 subjects with Turner 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) (Humatrope package insert).  The results with Nutropin were similar (Nutropin package insert). 

Renal Insufficiency

Growth hormone stimulates growth in prepubertal children with chronic renal failure and end stage renal disease and is FDA approved until time of renal transplantation.  Successful transplant should theoretically permit normal GH secretion and function.  Persistent growth failure post-transplant is primarily due to reduced graft function and glucocorticoid therapy.  The data for rhGH in short children post-transplant, although encouraging, is still short term, and concern regarding an increased rate of graft rejection in certain populations remains.

GH Therapy in Conjunction with GnRH Therapy as a Treatment of Precocious Puberty 

Precocious puberty is generally defined as the onset of secondary sexual characteristics before 8 years of age in girls and 9 years in boys.  Central precocious puberty is related to hypothalamic pituitary gonadal activation, leading to increase in sex steroid secretion, which accelerates growth and causes premature fusion of epiphyseal growth plates, thus impacting final height.  Children with precocious puberty are often treated with GnRH (gonadotropin releasing hormone) analogs to suppress the pituitary gonadal activity, to slow the advancement of bone age and to improve adult height.  Several long-term studies have reported that treatment with GnRH analogs is associated with improved adult height in most cases, particularly in those with the most accelerated bone age progression at treatment onset, the shortest predicted height, and the greatest difference between the target height and the predicted height (Adan, 2002; Manasco, 1989; Walvoord, 1999).  In contrast, subjects with a slowly progressive form in which the predicted height does not change after 2 years of follow-up may not require any treatment.  In another subset of subjects, GnRH analog therapy may be associated with a marked deceleration of bone growth that may ultimately result in an adult stature that is less than the targeted midparental height.  GH may be offered to these subjects in order to achieve the targeted adult height.  There has been only one randomized controlled trial comparing final adult height in those treated with GnRH analogs alone vs. GnRH analogs combined with growth hormone therapy (Tuvemo, 1999), and the largest case series includes 35 subjects.  Case series suggest that GH is most commonly offered as an adjunct to GnRH analogs when the growth velocity drops below the 25^th percentile for chronological age (Pucarelli, 2003; Tato, 1995).  A series of comparative case series studies 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 25^th percentile who were treated with a combination of GnRH and GH, and 18 girls who refused treatment with adjunctive GH (Pucarelli, 2003).  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.  Finally, Tuvemo and colleagues published the results of the only available randomized trial addressing the use of GH in conjunction with GnRH (Tuvemo, 1999).  This study included 46 girls with precocious puberty randomized 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 2 years of treatment, the mean growth and predicted adult height were greater in those receiving combined treatment compared to those receiving GnRH analogs alone.  The absence of final height data limits interpretation of this trial.

While other indications for GH without a documented GHD are considered reconstructive in nature, GH in conjunction with GnRH is considered investigational and not medically necessary due to the minimal published data. 

GH Therapy in Older Adults without Documented Growth Hormone Deficiency 

The GH secretion rate decreases by an estimated 14% per decade after young adulthood; mean levels in older adults are less than half those of a young adult.  However, mean GH levels in older adults are greater than age-matched adults with diagnosed 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 adults without organic pituitary disease.  The position regarding this off-label application is based on a review (TEC, 2001) and other publications (Biller, 2002; Am. Acad. Clin Endocrinologists, 2003), which offered the following observations and conclusions:

• In 2003, the American Academy of Clinical Endocrinologists (AACE) updated their published clinical guidelines regarding GH use (Am. Acad. Clin Endocrinologists, 2003).  Regarding the use of GH in adults, the AACE guidelines noted that "there is no place for the use of GH as an antiaging agent . . . [this use] should remain in experimental categories."  In the 2009 update of their recommendation, the AACE states: "In the United States, off-label distribution or marketing of GH to treat aging or aging-related conditions, and for the enhancement of athletic performance is illegal and punishable by imprisonment." See below in 'Other indications' for further information regarding this issue.
• Only 8 small controlled trials with at least 10 patients per treatment arm have examined the effect of GH therapy on older patients who may have partial GH deficiency.  Overall, these trials reported improved bone density, increased lean body mass, and decreased fat mass in rhGH-treated versus control arms.  However, results were not statistically significant and consistent across trials.  Information on physical performance and quality of life outcomes was insufficient to draw conclusions regarding functional and long-term benefits from rhGH treatment.  In 3 of 6 trials, noticeably fewer patients were evaluable in the treated than in the control arms.  All trials used starting rhGH doses that were above the currently recommended range.
• 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.  Currently limited results do not document clinically significant benefits with rhGH therapy, and they have potential for bias.  The available evidence is insufficient to determine whether rhGH improves health outcomes in adults with age-related GH deficiency.

GH Therapy as a Treatment of Altered Body Habitus Related to Antiretroviral Therapy for HIV Infection 

There has been research interest in the use of GH to treat the altered body habitus that may be a complication of antiretroviral therapy for HIV infection.  Body habitus changes, also referred to as the fat redistribution syndrome, include thinning of the face, thinning of the extremities, truncal obesity, breast enlargement, or an increased dorsocervical fat pad ("buffalo hump") (Lo 1998).  However, there is minimal published literature regarding the use of GH for this indication.  The literature is dominated by letters to the editors and small case series.  The largest case series was reported by Wanke and colleagues who treated 10 HIV-infected subjects with fat redistribution syndrome with GH for 3 months (Wanke, 1999).  The authors reported improved waist/hip ratio and mid-thigh circumference.

GH Therapy for Severe Burns 

A literature review for the use of human growth hormone for the treatment of burns found 9 published studies (8 randomized controlled trials, one case series).  Only one of the randomized controlled trials had a study population greater than 80.  All but two took place in the U.S.  Four of the studies were of adult subjects treated in the ICU, 3 involved pediatric ICU subjects and 2 involved pediatric subjects treated with GH for one year post-release from the hospital.  The results are mixed with 6 of the trials finding significant benefits of GH treatment and three trials finding no significant difference between GH treatment and controls.  Significant benefits reported include improved metabolic rates, healing times, cardiac function, length of stay (LOS) and decreased weight loss and mortality.  However, different benefits have been reported by different studies with only some overlap in findings.  Most studies reported a significantly higher proportion of GH-treated subjects developed hyperglycemia requiring insulin treatment, although the clinical significance is never discussed.  Of interest, two studies reported that other drugs, specifically oxandrolone (Demling, 1999) and propranolol (Heart, 2002), provided benefits equivalent to GH.  A third study (Przkora, 2005) reported on the outcomes of burn victims treated by oxandrolone vs. controls.  This study reports findings similar to those reported in their 2006 study (Przkora, 2006).  The two studies reporting on post-hospital care use of GH in pediatric burn subjects did report significant benefits, but the study populations are too small to allow generalization of the findings.

Overall, the evidence addressing the use of GH in the treatment of burns includes small studies with mixed results.  The findings reported in the positive studies are not consistent, with some reporting highly significant benefits in terms of mortality, healing times, and LOS, while others report no such benefits.  At this time the data does not support the use of GH for the treatment of burn subjects.  Further studies with larger populations are needed to resolve issues regarding the inconsistencies detailed above. 

GH Therapy in Conjunction with Optimal Management of Short Bowel Syndrome 

Short bowel syndrome is experienced by individuals 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 subjects dependent on intravenous parenteral nutrition who received Zorbtive (either with or without glutamine) over a 4-week period had significantly greater reductions in the weekly total volume of intravenous parenteral nutrition required for nutritional support.  However, the effects beyond 4 weeks were not evaluated nor was the treatment location (inpatient vs. outpatient) identified.  Several published studies have also demonstrated improved intestinal absorption in short bowel syndrome subjects receiving parenteral nutrition (Scolapio 1999; Wu, 2003).  However, studies have noted the effects of increased intestinal absorption are limited to the treatment period (Seguy, 2003; Szkudlarek, 2000; Wu, 2003).  Specialized clinics may offer intestinal rehabilitation for individuals with short bowel syndrome; GH may be one component of this therapy. 

Other Indications

GH therapy has been investigated for use in the treatment of many different conditions, including cystic fibrosis, idiopathic dilated cardiomyopathy, and juvenile idiopathic arthritis (Adamopoulos, 2003; Albert, 2004; Bechtold, 2003; Darmaun, 2004; Schibler, 2003).  No randomized clinical trials were identified to sufficiently demonstrate the appropriateness of GH therapy in these conditions.

Finally, it must be noted that the prescribing of growth hormone is limited to FDA approved indications by the U.S. Federal Food, Drug and Cosmetic Act, Sec. 301. [21 U.S.C. §303(e)]:
Prohibited distribution of human growth hormone.

1. Except as provided in paragraph (2), whoever knowingly distributes, or possesses with intent to distribute, human growth hormone for any use in humans other than the treatment of a disease or other recognized medical condition, where such use has been authorized by the Secretary of Health and Human Services under section 505 and pursuant to the order of a physician, is guilty of an offense punishable by not more than 5 years in prison, such fines as are authorized by title 18, United States Code, or both.
2. Whoever commits any offense set forth in paragraph (1) and such offense involves an individual under 18 years of age is punishable by not more than 10 years imprisonment, such fines as are authorized by title 18, United States Code, or both.
3. Any conviction for a violation of paragraphs (1) and (2) of this subsection shall be considered a felony violation of the Controlled Substances Act for the purposes of forfeiture under section 413 of such Act.
4. As used in this subsection the term "human growth hormone" means somatrem, somatropin, or an analogue of either of them.
5. The Drug Enforcement Administration is authorized to investigate offenses punishable by this subsection.

Introduction
Production of growth hormone (GH), the most abundant anterior pituitary hormone, begins early in fetal life and continues throughout life, although at a progressively lower rate.  GHD may be idiopathic or caused by a variety of organic conditions, including, but not limited to, pituitary stalk or gland defect, GH gene mutation, and intracranial tumor.  GHD may also be acquired due to hypothalamic-pituitary damage such as may be caused by treatment for intracranial tumor or leukemia, which generally involve surgery, radiotherapy, or chemotherapy.

Originally, the limited supply of human GH restricted its use to those children with growth hormone deficiency.  However, the advent of recombinant GH prompted interest in expanding the indications of GH therapy for those with short stature without an associated GH deficiency, idiopathic short stature (ISS), chronic renal insufficiency, Turner syndrome, Noonan's syndrome, small for gestational age (SGA)/intrauterine growth retardation, Russell-Silver syndrome, and Prader-Willi syndrome.  The anti-catabolic properties of growth hormone have also led to investigation of use in cystic fibrosis and severe burn injury.  The effectiveness of GH therapy in children has primarily been judged by whether it increases growth rate and/or final height. 

Growth Hormone Therapy in Children
In the absence of known pituitary or hypothalamic pathology, GHD is usually first suspected on the basis of height and growth velocity.  A period of at least one year of data is necessary for reliable calculation of growth velocity of children above the age of two years.  GHD in children is suggested when there is an abnormal growth velocity in conjunction with a height and bone age that is less than chronological age for gender.

Provocative testing remains a standard in confirmation of a diagnosis of GHD and requires a subnormal response.  Since not one GH stimulation test has 100% sensitivity and 100% specificity, most countries have established an arbitrary cut off for a normal peak serum GH response (usually >8 to 10 ng/L) to at least two provocative GH stimulation tests.  There is growing consensus amongst endocrinologists that a diagnosis of impaired GH secretion can be confirmed if subnormal GH secretion is observed during one test in addition to clinical and auxologic (growth data for height and weight plotted on a growth chart) criteria.  The stimulation test parameters used to determine GHD are higher in the pediatric population than the adult population as pediatric individuals show a more robust response to stimulation.

Studies suggest that discontinuation of GH therapy upon reaching final adult height in individuals with severe GHD may contribute to an accelerated accumulation of cardiovascular risk factors.  While certain types of pediatric individuals with GHD (organic hypothalamic-pituitary disease, additional pituitary deficiency, or post-irradiation GHD) are more likely than others to have continued GHD into adulthood, retesting a minimum of 3 months after discontinuing previous GH therapy is required to confirm persistent GHD.

Chronic Renal Insufficiency
Growth failure in children with chronic renal insufficiency is thought to be multifactorial, with one of the factors being reduced sensitivity to GH rather than GH insufficiency.  Growth hormone therapy has been shown to stimulate growth in prepubertal children with chronic renal insufficiency.  Prior to initiation of GH treatment, existing metabolic derangements such as malnutrition, zinc deficiency, and secondary hyperparathyroidism should be corrected.

Prader-Willi syndrome
Children with Prader-Willi syndrome are considered to have a hypothalamic disorder and GH therapy is intended to replace physiological levels of GH.  Additionally, growth hormone replacement may partially alleviate some of the metabolic complications associated with Prader-Willi syndrome, helping normalize height and also increase lean body mass, both of which help weight management.  Prescribing physicians should be aware of an FDA alert concerning post marketing reports of fatalities with the use of growth hormone in children with Prader-Willi Syndrome.  These individuals had one or more of the following risk factors: severe obesity, history of respiratory impairment or sleep apnea, or unidentified respiratory infection.

Turner syndrome
Turner syndrome (gonadal dysgenesis) describes an XO phenotype (i.e., one sex chromosome is missing), and physically is characterized by absent or severely delayed sexual development.  Growth delay is present in virtually all females with this disorder with the reported average final height of 4'7'' to 4'10".  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.

Noonan's syndrome
Noonan's syndrome is a form of congenital dysgenesis that occurs with approximately equal incidence in males and females.  It is characterized by a variety of cardiopulmonary, dermatologic, neurologic, renal, ocular, coagulation, and vascular abnormalities occurring at varying incidences, as well as disturbances in linear and skeletal growth that may lead to a variety of physical deformities.  Short stature is present in approximately 80% of the subjects affected and puberty is generally delayed.  Due to several shared characteristics, Noonan's syndrome is sometimes called pseudo Turner syndrome.  However, unlike Turner syndrome, there is no known chromosomal cause, and infertility and intrauterine growth retardation are not characteristic.  Instead, growth delay is first noticed in infancy, and bone age consistently lags approximately 2 years behind chronological age.  While the bone-age delay extends the period of linear growth beyond the normal age when growth is complete, final height is generally below normal at a mean of 162.5 cm for males and 151 cm for females (176 cm and 163 cm, respectively, in the United States).  Most children with Noonan's syndrome are not GH deficient but may have defects in the GH/IGF-I axis.

Children Small for Gestational Age
Infants born at a weight and/or length of more than two standard deviations (SDS) below the mean for their gestational age at birth may be classified either as being SGA or as having intrauterine growth retardation (IUGR).  Most children who are SGA experience catch-up growth and achieve a height >2 SD below the mean; this catch-up process is usually completed by the time they are 2 years of age.  A child who is SGA and older than 3 years and has persistent short stature is not likely to catch-up.  Persistent growth failure in children with SGA only rarely involves classic GHD but is frequently associated with abnormalities in the GH secretory pattern, such as a reduced or increased GH pulse frequency or amplitude, a reduced 24-hour GH concentration, GH insufficiency in response to GHRH stimulation, or low levels of IGF-I.

Idiopathic short Stature 

In childhood and adolescence, growth hormone therapy is typically initiated when the parameters of growth indicate that the predicted final height of the child is considered below the normal range and when testing indicates an abnormality of growth hormone production.  Since short stature is not associated with a definable physical functional impairment (e.g., limiting ability to drive), and is not due to growth hormone deficiency, this indication for growth hormone therapy is considered reconstructive in nature.

Growth Hormone Therapy in Adults
In adults, the syndrome of GHD characteristically manifests as: deficiencies in bone mineral density; reduced muscle strength and exercise capacity; abnormal body composition with reduced lean body mass and increased body fat; higher lipid concentration; impaired psychological well being; anxiety; and increased social isolation.  Literature shows that over 90% of adults with GHD have overt pituitary disease, which is usually caused by a pituitary adenoma, or by surgery or radiation therapy for a pituitary adenoma.  Adults with idiopathic, isolated childhood-onset GHD must be re-tested before long-term replacement therapy is initiated as childhood GHD frequently does not persist into the adult years.

The state of decreased growth hormone in otherwise normal aging adults who are not congenitally GH deficient and who have no evidence of organic pituitary disease is referred to as "age-related GH deficiency" (AR-GHD).  Older adults tend to have reduced GH secretion compared to younger adults and by age 70 it is estimated that GH levels are 20% of those seen at age 30.  A number of age-associated changes, including an increase in body fat, loss of muscle mass, decrease in bone mineral density, and reduced cardiac performance, resemble those seen in younger adults with biochemically verified GHD.  The controversy lies in whether decreased GH levels in older adults are "normal" or a sign of a deficient hormonal state.  The administration of GH to AR-GHD individuals has resulted in improvements in some intermediate outcomes such as bone mineral density and body composition but results are not consistent across trials and the relationship of these intermediate outcomes to long term health outcomes has not been established.  The limited results do not suggest marked improvement with GH therapy and are insufficient to permit conclusions regarding the effectiveness of GH in improving quality of life for adults with AR-GHD.

AIDS Wasting
The FDA approved growth hormone for treatment of wasting or cachexia in individuals with acquired immunodeficiency syndrome (AIDS) in 1996.  This approval was based on evidence that growth hormone increased lean body mass and decreased fat mass in individuals with AIDS, although no survival benefit was observed.  This drug must be used in conjunction with antiretroviral therapy.  The recommended duration of treatment is 12 weeks.  No significant additional treatment benefit was observed in individuals receiving therapy beyond 12 weeks.  There are no data available from studies for individuals who start, stop and restart treatment.

The use of growth hormone has also been studied in small numbers of adults with other catabolic illnesses, including those associated with respiratory failure, recovery from surgery, congestive cardiomyopathy, liver transplantation, and renal failure.  No consistent benefit has yet been demonstrated.  Growth hormone has been given to individuals with obesity, osteoporosis, muscular dystrophy, and infertility, but with no consistent benefit.

Bone age: The relative maturity of a child's skeletal system compared to standards for chronological age.  Bone age tests are performed by x-raying several growth centers -usually the wrist and elbow- and comparing to standards for normal, for boys and girls, in three-month increments by chronological age.  The most common use in office practice is to determine a short child's growth potential.

Constitutional growth delay: Characterized by normal prenatal growth followed by growth deceleration during childhood resulting in declining height percentiles. These children are small for their age due to delayed bone age. However they still grow at a normal rate.  Children with constitutional delay have later timing of puberty, which allows a longer period for growth; most commonly, normal adult height is achieved if no treatment is given.

Epiphyses: End parts of certain bones, which come together when final height is reached.

Genetic (familial) short stature: Short children with normal growth velocity, normal skeletal maturation, normal response to GH provocative testing, and predicted adult height falls within range of expected height based on height of parents.

Growth hormone (GH): Is available as an artificially produced version of the natural hormone (also know as rhGH) where "r" is for recombinant, meaning artificially produced in the lab, "h" is for human).  GH must be injected under the skin either daily or several times per week. 

Hypopituitarism: Condition that occurs when several pituitary hormones are not being secreted normally. 

Idiopathic: A specific condition not preceded or caused by any other disease. 

Russell-Silver Syndrome (RSS): Included among those with SGA and slowed postnatal growth is a subgroup of children with RSS, a disorder characterized by feeding difficulties and dysmorphic features such as limb asymmetry, triangular face, deflection of one or more fingers, and short stature.  Some individuals with RSS may have documented traits while others have very few.

Sexual Maturity Rating (SMR, Tanner Stage): A commonly used measurement of sexual maturity in children, based upon the work of Tanner et al. (1962).  SMR is based upon clinical findings from physical examination of the individual, as detailed below:

Classification of Sex Maturity States in Girls*

Classification of Sex Maturity States in Boys*

*From Tanner JM: Growth at Adolescence, 2nd ed. Oxford, England, Blackwell Scientific Publications, 1962. SMR, sexual maturity rating, and Marcell AV. Chapter 12- Adolescence. In: Kliegman RM, Behrman RE, Jenson HB, Stanson BF, Editors. Nelson Textbook of Pediatrics. 18th Ed. St. Louis, MO: WB. Saunders, Inc. 2007. 

Short stature: Short stature has been variably defined although commonly is considered to be those who are in the 3^rd percentile of height for their age and gender.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. 

When services may be Medically Necessary when criteria are met:

When Services may be Reconstructive when criteria are met:
For the procedure codes listed above for the following diagnoses; or when the code describes a procedure indicated in the Position Statement section as reconstructive:

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met, for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Adamopoulos S, Parissis JT, Paraskevaidis I, et al. Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy. Eur Heart J. 2003; 24(24):2186-2196. 
2. Adan L, Chemaitilly W, Trivin C, Brauner R.  Factors predicting adult height in girls with idiopathic central precocious puberty: implications for treatment.  Clin Endocrinol (Oxf). 2002; 56(3):297-302. 
3. Aimaretti G, Ambrosio MR, Di Somma C, et al. Traumatic brain injury and subarachnoid haemorrhage are conditions at high risk for hypopituitarism: screening study at 3 months after the brain injury. Clin Endocrinol (Oxf). 2004; 61(3):320-326.
4. Albert SG, Mooradian AD. Low-dose recombinant human growth hormone as adjuvant therapy to lifestyle modifications in the management of obesity. J Clin Endocrinol Metab. 2004; 89(2):695-701. 
5. Allen DB, Carrel AL. Growth hormone therapy for Prader-Willi syndrome: a critical appraisal. J Pediatr Endocrinol Metab. 2004; 17(suppl 4):1297–1306.
6. Allen DB. Growth hormone therapy for short stature: is the benefit worth the burden? Pediatrics. 2006; 118(1):343-348.
7. Bechtold S, Ripperger P, Hafner R, et al.  Growth hormone improves height in patients with juvenile idiopathic arthritis: 4-year data of a controlled study.  J Pediatr. 2003; 143(4):512-519. 
8. Bidlingmaier M, Strasburger CJ.  Growth hormone assays: current methodologies and their limitations. Pituitary. 2007; 10(2):115-119.
9. Biller BM, Samuels MH, Zagar A, et al.  Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab. 2002; 87(5):2067-2079.
10. Blum WF, Cao D, Hesse V, et al. Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome. Horm Res. 2009; 71(3):167-172.
11. Carrel AL, Moerchen V, Myers SE, et al. Growth hormone improves mobility and body composition in infants and toddlers with Prader-Willi syndrome. J Pediatr. 2004; 145(6):744-749.
12. Carrel AL, Myers SE, Whitman BY, Allen DB.  Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study. J Clin Endocrinol Metab. 2002; 87(4):1581-1585.
13. Cittadini A, Saldamarco L, Marra AM, et al. Growth hormone deficiency in patients with chronic heart failure and beneficial effects of its correction. J Clin Endocrinol Metab. 2009; 94(9):3329-3336.
14. Conway GS, Szarras-Czapnik M, Racz K, et al. GHD to GHDA Transition Study Group. Treatment for 24 months with recombinant human GH has a beneficial effect on bone mineral density in young adults with childhood-onset GH deficiency. Eur J Endocrinol. 2009; 160(6):899-907.
15. Darmaun D, Hayes V, Schaeffer D, et al.  Effects of glutamine and recombinant human growth hormone on protein metabolism in prepubertal children with cystic fibrosis.  J Clin Endocrinol Metab. 2004; 89(3):1146-1152. 
16. Davenport ML, Crowe BJ, Travers SH, et al. Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial. J Clin Endocrinol Metab. 2007; 92(9):3406-3416.
17. de Lind van Wijngaarden RF, Festen DA, Otten BJ, et al. Bone mineral density and effects of growth hormone treatment in prepubertal children with Prader-Willi syndrome: a randomized controlled trial. J Clin Endocrinol Metab. 2009; 94(10):3763-3771.  
18. Demling RH. Comparison of the anabolic effects and complications of human growth hormone and the testosterone analog, oxandrolone, after severe burn injury.  Burns. 1999; 25(3):215-221.
19. Finkelstein BS, Imperiale TF, Speroff T, et al.  Effect of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis.  Arch Pediatr Adolesc Med. 2002; 156(3):230-240.
20. Haqq AM, Stadler DD, Jackson RH, et al. Effects of growth hormone on pulmonary function, sleep quality, behavior, cognition, growth velocity, body composition, and resting energy expenditure in Prader-Willi syndrome. J Clin Endocrinol Metab. 2003; 88(5):2206-2212.
21. Hart DW, Wolf SE, Chinkes DL, et al.  Beta-blockade and growth hormone after burn.  Ann Surg. 2002; 236(4):450-456.
22. Herndon DN, Barrow RE, Kunkel KR, et al.  Effect of recombinant human growth hormone on donor-site healing in severely burned children.  Ann Surg. 1990; 212(4):424-429.
23. Knox J, Demling R, Wilmore D, et al.  Increased survival after major thermal injury: the effect of growth hormone therapy in adults.  J Trauma. 1995; 39(3):526-530.
24. Lindgren AC, Hellstrom LG, Ritzen EM, Milerad J. Growth hormone treatment increases CO(2) response, ventilation and central inspiratory drive in children with Prader-Willi syndrome. Eur J Pediatr. 1999; 158(11):936-940.
25. Lo JC, Mulligan K, Tai VW, et al.  "Buffalo hump" in men with HIV-1 infection.  Lancet. 1998; 351(9106):867-874.
26. Losada F, Garcia-Luna PP, Gomez-Cia T, et al.  Effects of human recombinant growth hormone on donor-site healing in burned adults.  World J Surg. 2002; 26(1):2-8.
27. Manasco PK, Pescovitz OH, Hill SC, et al.  Six-year results of luteinizing hormone releasing hormone (LHRH) agonist treatment in children with LHRH-dependent precocious puberty.  J Pediatr. 1989; 115(1):105-108.
28. Myers SE, Whitman BY, Carrel AL, et al. Two years of growth hormone therapy in young children with Prader-Willi syndrome: physical and neurodevelopmental benefits. Am J Med Genet A. 2007; 143(5):443-448.
29. Obata K, Sakazume S, Yoshino A, et al. Effects of 5 years growth hormone treatment in patients with Prader-Willi syndrome. J Pediatr Endocrinol Metab. 2003; 16(2):155–162.
30. Pasquino AM, Pucarelli I, Roggini M, Segni M. Adult height in short normal girls treated with gonadotropin- releasing analogs and growth hormone.  J Clin Endocrinol Metab. 2000; 85(2):619-622.
31. Pasquino AM, Pucarelli I, Segni M, et al. Adult height in girls with central precocious puberty treated with gonadotropin-releasing hormone analogues and growth hormone.  J Clin Endocrinol Metab. 1999; 84(2):449-452.
32. Przkora R, Herndon DN, Suman OE, et al.  Beneficial effects of extended growth hormone treatment after hospital discharge in pediatric burn patients. Ann Surg. 2006; 243(6):796-801.
33. Przkora R, Jeschke MG, Barrow RE, et al.  Metabolic and hormonal changes of severely burned children receiving long-term oxandrolone treatment. Ann Surg. 2005; 242(3):384-399.
34. Pucarelli I, Segni M, Ortore M, et al.  Effects of combined gonadotropin-releasing hormone agonist and growth hormone therapy on adult height in precocious puberty: a further contribution. J Pediatr Endocrinol Metab. 2003; 16(7):1005-1010.
35. Ramirez RJ, Wolf SE, Barrow RE, Herndon DN. Growth hormone treatment in pediatric burns: a safe therapeutic approach.  Ann Surg. 1998; 228(4):439-448.
36. Saggese G, Cesaretti G, Barsanti S, Rossi A. Combination treatment with growth hormone and gonadotropin-releasing hormone analogs in short normal girls.  J Pediatr. 1995; 126(3):468-473. 
37. Sandberg DE, Brook AE, Campos SP.  Short stature: a psychosocial burden requiring growth hormone therapy?  Pediatrics. 1994; 94(6 Pt 1):832-840.
38. Savastano S.  Benefits from growth hormone therapy after bariatric surgery. Pediatr Endocrinol Rev. 2009; 6 Suppl 4:540-544.
39. Savastano S, Di Somma C, Angrisani L, et al. Growth hormone treatment prevents loss of lean mass after bariatric surgery in morbidly obese patients: results of a pilot, open, prospective, randomized, controlled study. J Clin Endocrinol Metab. 2009; 94(3):817-826.
40. Schibler A, von der Heiden R, Birrer P, Mullis PE. Prospective randomized treatment with recombinant human growth hormone in cystic fibrosis. Arch Dis Child. 2003; 88(12):1078-1081. 
41. Scolapio JS.  Effect of growth hormone, glutamine, and diet on body composition in short bowel syndrome: a randomized, controlled study.  JPEN J Parenter Enteral Nutr. 1999; 23(6):309-312. 
42. Seguy D, Vahedi K, Kapel N, et al.  Low-dose growth hormone in adult home parenteral nutrition-dependent short bowel syndrome patients: a positive study.  Gastroenterology. 2003; 124(2):293-302. 
43. Singh KP, Prasad R, Chari PS, Dash RJ.  Effect of growth hormone therapy in burn patients on conservative treatment. Burns. 1998; 24(8):733-738.
44. Szkudlarek J, Jeppesen PB, Mortensen PB.  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; 47(2):199-205.
45. Takala J, Ruokonen E, Webster NR, et al.  Increased mortality associated with growth hormone treatment in critically ill adults.  N Engl J Med. 1999; 341(11):785-792.
46. Tanaka T, Satoh M, Yasunaga T, et al.  When and how to combine growth hormone with a luteinizing hormone-releasing hormone analogue.  Acta Paediatr Suppl. 1999; 88(428):85-88.
47. Tato L, Saggese G, Cavallo L, et al.  Use of combined Gn-RH agonist and hGH therapy for better attaining the goals in precocious puberty treatment.  Horm Res. 1995; 44(Suppl 3):49-54. 
48. Tuvemo T, Gustafsson J, Proos LA.  Growth hormone treatment during suppression of early puberty in adopted girls. Acta Paediatr. 1999; 88(9):928-932.
49. Walvoord EC, Pescovitz OH.  Combined use of growth hormone and gonadotropin-releasing hormone analogues in precocious puberty: theoretic and practical considerations.  Pediatrics. 1999; 104(4 Pt 2):1010-1014. 
50. Wanke C, Gerrior J, Kantaros J, et al. Recombinant human growth hormone improves the fat redistribution syndrome (lipodystrophy) in patients with HIV.  AIDS. 1999; 13(15):2099-2013.
51. Wu GH, Wu ZH, Wu ZG.  Effects of bowel rehabilitation and combined trophic therapy on intestinal adaptation in short bowel patients.  World J Gastroenterol. 2003; 9(11):2601-2614.

Government Agency, Medical Society, and Other Authoritative Publications:

1. AACE Growth Hormone Task Force.  American Association of Clinical Endocrinologists medical guidelines for hormone use in adults and children—2003 update.  Endocrine Practice. 2003; 9(1):65-76.
2. Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment Number 72. Criteria for Determining Disability in Infants and Children: Failure to Thrive. March, 2003. Available at: http://www.ahrq.gov/downloads/pub/evidence/pdf/failthrive/failthrive.pdf.  Accessed on March 11, 2011.
3. Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment Number 73. Criteria for determining disability in infants and children: short stature. March, 2003. Available at: http://www.ahrq.gov/downloads/pub/evidence/pdf/short/short.pdf.  Accessed on March 11, 2011.
4. Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment Number 70. Criteria for determining disability in infants and children: Low Birth Weight. December, 2002. Available at: http://www.ahrq.gov/downloads/pub/evidence/pdf/lbw/lbw.pdf.  Accessed on March 11, 2011.
5. Agency for Healthcare Research and Quality. Effectiveness of Recombinant Human Growth Hormone (rhGH) in the Treatment of Patients with Cystic Fibrosis. Comparative Effectiveness Review Number 23. October 2010. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=391.  Accessed on March 11, 2011.
6. American Academy of 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; 99(1):122–129.
7. Baxter L, Bryant J, Cave CB, Milne R. Recombinant growth hormone for children and adolescents with Turner syndrome. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD003887.
8. Blue Cross Blue Shield Association. Recombinant Human Growth Hormone (GH) Therapy in Adults with Age-Related GH Deficiency. TEC Assessment, 2001; 16(11).
9. Bryant J, Cave C, Milne R. Recombinant growth hormone for idiopathic short stature in children and adolescents. Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD004440.
10. Cave CB, Bryant J, Milne R. Recombinant growth hormone in children and adolescents with Turner syndrome. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD003887.
11. Cohen P, Rogol AD, Deal CL, et al.;  the 2007 ISS Consensus Workshop participants. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: Asummary of the growth hormone research society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology workshop. J Clin Endocrinol Metab. 2008; 93:4210–4217.
12. Cook DM, Yuen KC, Biller BM, 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: executive summary of recommendations. Endocr Pract. 2009; 15(Suppl 2):1-29. Available at http://www.aace.com/pub/pdf/guidelines/GrowthHormoneGuidelines.pdf. Accessed on March 11, 2011.
13. Duffy JMN, Ahmad G, Mohiyiddeen L, Nardo LG, Watson A. Growth hormone for in vitro fertilization. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD000099.
14. Genotropin^®_,Package Insert.
15. Harper K, Proctor M, Hughes E. Growth hormone for in vitro fertilization. Cochrane Database of Systematic Reviews 2003, Issue 3. Art. No.: CD000099.
16. Huiming Y, Meng M, Chaomin W, Fan Y. Recombinant growth hormone therapy for X-linked hypophosphatemia in children. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD004447.
17. Humatrope, Package Insert.
18. Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P; International Small for Gestational Age Advisory Board. International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24-October 1, 2001. Pediatrics. 2003; 111(6 Pt 1):1253-1261.
19. Marcell AV. Chapter 12- Adolescence. In: Kliegman RM, Behrman RE, Jenson HB, Stanson BF, Editors. Nelson Textbook of Pediatrics. 18^th Ed. St. Louis, MO: WB. Saunders, Inc. 2007.
20. Molitch ME, Clemmons DR, Malozowski S, et al.  Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2006; 91(5):1621-1634.
21. Norditropin^® [Product information], Princeton, NJ. Novo Nordisk Inc. February, 2004. Available at: http://www.novonordisk.com/therapy_areas/growth_hormone/hcp/devices/nordiflex/prescribing_info.asp. . Accessed on March 11, 2011.
22. Nutropin^®_,Package Insert.
23. Omnitrope^®_,Package Insert.
24. Saizen^® [Product information], Rockland, MD. Serono Inc. July 1993. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019764s035lbl.pdf.  Accessed on May 13, 2010.
25. Sandostatin^® [Product information], Basel, Switzerland.  Novartis AG. November 1998. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019667s054lbl.pdf.  Accessed May 13, 2010.
26. Serostim^® [Product information], Serono, Inc., Randolph, MA. August, 2003. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020604s044_2lbl.pdf. Accessed on March 18, 2011.
27. Tanner JM. Growth at Adolescence, 2nd ed. Oxford, England, Blackwell Scientific Publications, 1962. SMR, sexual maturity rating.
28. U.S. Federal Food and Drug Administration. Recombinant Human Growth Hormone (somatropin): Ongoing safety review - Possible increased risk of death. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm237969.htm. Accessed on March 11, 2011.
29. U.S. Federal Food, Drug and Cosmetic Act, Sec. 301. [21 U.S.C. §303(e)]. Available at: http://www.fda.gov/opacom/laws/fdcact/fdcact3.htm.  Accessed on March 18, 2011.
30. Vimalachandra D, Hodson EM, Willis NS, Craig JC, Cowell C, Knight JF. Growth hormone for children with chronic kidney disease. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD003264.
31. Wales PW, Nasr A, de Silva N, Yamada J. Human growth hormone and glutamine for patients with short bowel syndrome. Cochrane Database of Systematic Reviews 2010, Issue 6. Art. No.: CD006321.
32. Wilson TA, Rose SR, Cohen P, et al. Update of guidelines for the use of growth hormone in children: the Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee. J Pediatr. 2003; 143(4):415-421.
33. Yang HM, Mao M, Yang F, Wan CM. Recombinant growth hormone therapy for X-linked hypophosphatemia in children. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD004447.

1. Centers for Disease Control and Prevention (CDC) National Center for Health Statistics. CDC Growth Charts United States. Available at: http://www.cdc.gov/growthcharts/. Accessed on March 11, 2011. 

Genotropin^®
hGH-CTP
Humatrope^®
Norditropin^®
Nutropin^®
Omnitrope^®
Saizen^®
Serostim^®
Somatropin
Tev-Tropin^®
Zorbtive^®

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.