Clinical UM Guideline


Subject: Growth Hormone
Guideline #: CG-DRUG-83 Publish Date:    02/27/2019
Status: Reviewed Last Review Date:    01/24/2019


This document addresses the use of human growth hormone (GH) 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. §333(e)], Growth Hormone may not be legally distributed for any condition not approved by the U.S. Food and Drug Administration (FDA).*

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.

Note: Please see the following document for additional information regarding the treatment of IGF-1 deficiency and GH insensitivity:

Clinical Indications


A.  Medically Necessary

Growth hormone replacement therapy is considered medically necessary for children with documentation demonstrating the presence of any one of the following conditions:

  1. Idiopathic growth hormone deficiency (GHD) as indicated by BOTH a) and b) below:
    1. The child has signs or symptoms of growth hormone deficiency such as growth velocity 2 Standard Deviations (SD) below age-appropriate mean or height 2.25 SD below the age-appropriate mean; and
    2. A subnormal response (less than 10 ng/ml) to any TWO of the following standard growth hormone stimulation tests: 
      1. Arginine;
      2. Clonidine;
      3. Glucagon;
      4. Insulin induced hypoglycemia;
      5. L-dopa - Propranolol; or
  2. Documented presence of at least two other pituitary hormone* deficiencies, in addition to Insulin-like growth factor 1 (IGF-1) measurement below age-appropriate level; or
  3. Neonates with hypoglycemia and clinical and hormone evidence of hypopituitarism (growth hormone level less than 10 ng/ml); or
  4. Children who have had cranial irradiation and have documented evidence of IGF-1 measurement below age-appropriate level with normal thyroid function tests results.

* Please see the definitions section below for a full list of pituitary hormones

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 either of the following:
    1. 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 10th percentile over 1 year; or
    2. 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:
    1. Chronic renal insufficiency; or
    2. 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
    3. Noonan syndrome; or
    4. Turner syndrome; or
    5. Children with Short Stature Homeobox (SHOX) gene; or
    6. Children born small for gestational age defined as all of the following:
      1. 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
      2. 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
      3. 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 (either medically necessary or reconstructive), and, if reconstructive, have not met the requirements for termination of GH therapy described in Section D below: 

  1. 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
  2. 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
  3. 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
  4. For children over age 12, either of the following:
    1. An X-ray report with evidence that epiphyses have not yet closed (does not apply to children with prior documented hypopituitarism); or
    2. 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:

  1. Bone age = 16 years (male), or = 14 years (female) is reached; or
  2. Epiphyseal fusion has occurred; or
  3. “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 1 month; and the diagnosis of GHD has been reconfirmed as follows:
    1. 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-1/IGFBP-3; or
    2. For individuals with multiple pituitary hormone deficiencies, a documented subnormal response* to one provocative GH test or low IGF-1/IGFBP-3; or
    3. For individuals who have had cranial irradiation, continued documentation of IGF-1 measurement below age-appropriate level with normal thyroid function test results; 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 (growth hormone stimulation tests are not required):
    1. A known genetic mutation associated with deficient growth hormone production or secretion; or
    2. Hypothalamic-pituitary tumor or structural defect; or
    3. At least three other pituitary hormone deficiencies.


A.  Medically Necessary

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:

  1. 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
  2. Subnormal response to one stimulation test for adults with documented hypothalamic or pituitary disease and one or more additional pituitary hormone deficits; or
  3. Documented presence of at least three other pituitary hormone deficiencies (that is, growth hormone stimulation tests are not required in this subgroup of individuals).

B.  Not Medically Necessary

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).


Medically Necessary

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.


Medically Necessary

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.


A.  Not Medically Necessary:

Growth hormone therapy to increase height in children with idiopathic short stature is considered not medically necessary.  

Growth hormone therapy is considered not medically necessary for children who do not have signs or symptoms of idiopathic GHD (for example, reduced height or growth velocity), unless a) criteria for other pituitary hormone deficiencies are met or b) criteria for neonate with hypoglycemia are met or c) criteria for cranial irradiation are met (Note: an individual who does not meet medical necessity criteria may meet reconstructive criteria).

Growth hormone replacement therapy is considered not medically necessary for children who no longer meet the continuation of growth hormone therapy criteria above.

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

  1. After renal transplant.
  2. Anabolic therapy, except for AIDS, provided to counteract acute or chronic catabolic illness (for example, surgery, trauma, cancer, chronic hemodialysis) producing catabolic (protein wasting) changes in both adults and children.
  3. Anabolic therapy to enhance body mass or strength for professional, recreational or social reasons.
  4. Constitutional delay of growth and development.
  5. Cystic fibrosis.
  6. Growth hormone treatment in combination with GnRH agonist (Lupron) as a treatment of precocious puberty.
  7. Hypophosphatemic rickets.
  8. Osteogenesis imperfecta.
  9. Osteoporosis.
  10. Short stature associated with growth hormone insensitivity (Laron Syndrome).
  11. 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).
  12. Treatment of congestive heart failure (CHF).
  13. Treatment of individuals with burns.
  14. Treatment of fibromyalgia.
  15. Treatment of glucocorticoid-induced growth failure.
  16. Treatment of HIV lipodystrophy (fat redistribution syndrome), also referred to as altered body habitus (for example, buffalo hump), associated with antiviral therapy in individuals with HIV-infection.
  17. Treatment of intrauterine growth restriction (IUGR) or Russell-Silver Syndrome that does not result in SGA.
  18. Treatment of obesity.
  19. 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 not medically necessary in all cases.

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


The following codes for treatments and procedures applicable to this guideline 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.




Injection, somatrem, 1 mg


Injection, somatropin, 1 mg [Genotropin, Humatrope, Norditropin, Nutropin, Nutropin AQ, Omnitrope, Saizen, Serostim, Zomacton, Zorbtive]


Injection, sermorelin acetate, 1 microgram


Home injectable therapy; growth hormone, including administrative services, professional pharmacy services, coordination of care, and all necessary supplies and equipment, per diem



ICD-10 Diagnosis



Human immunodeficiency virus [HIV] disease


Malignant neoplasm of cerebrum, except lobes and ventricles [specified as hypothalamus]


Malignant neoplasm of pituitary gland


Benign neoplasm of brain, supratentorial [specified as hypothalamus]


Benign neoplasm of pituitary gland


Neoplasm of uncertain behavior of brain, supratentorial [specified as hypothalamus]


Neoplasm of uncertain behavior of pituitary gland


Hypofunction and other disorders of the pituitary gland


Other specified metabolic disorders [e.g., when related to hypothalamic dysfunction]


Nontraumatic subarachnoid hemorrhage


Postsurgical malabsorption, not elsewhere classified [short bowel syndrome]


Chronic kidney disease (CKD)


Renal osteodystrophy


Newborn light for gestational age


Newborn small for gestational age


Newborn affected by slow intrauterine growth, unspecified


Other osteochondrodysplasia with defects of growth of tubular bones and spine [Leri-Weill syndrome, SHOX gene deficiency]


Congenital malformation syndromes predominantly associated with short stature [when specified as Prader-Willi syndrome, Noonan syndrome, Russell-Silver syndrome]


Turner’s syndrome


Delayed milestone in childhood


Short stature (child) [only when specified as related to SHOX gene deficiency]

Note: Considered Note Medically Necessary when specified as idiopathic short stature




Traumatic subarachnoid hemorrhage, sequela [includes codes S06.6X0S, S06.6X1S, S06.6X2S, S06.6X3S, S06.6X4S, S06.6X5S, S06.6X9S]


Other specified intracranial injury, sequela [includes codes S06.890S, S06.891S, S06.892S, S06.893S, S06.894S, S06.895S, S06.899S]


Radiation sickness, unspecified, sequela


Personal history of malignant neoplasm of brain


Personal history of nephrotic syndrome


Personal history of other diseases of urinary system


Dependence on renal dialysis

Discussion/General Information


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, such as 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 1 year of data is necessary for reliable calculation of growth velocity of children above the age of 2 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-1 axis.

Children Small for Gestational Age

Infants born at a weight and/or length of more than 2 standard deviations (SD) 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 GH releasing hormone (GHRH) stimulation, or low levels of IGF-1.

Idiopathic Short Stature

Growth hormone therapy may be initiated when the parameters of growth suggest that the predicted final height of the child will be below the normal range.  Short stature is not associated with a definable physical functional impairment (e.g., limiting ability to drive), is not due to growth hormone deficiency, and is not the result of accidental injury, disease, trauma, or treatment of a disease and is not a congenital defect.  Therefore, this use of growth hormone therapy is considered not medically necessary.

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.

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.


Concepts of Medically Necessary and Reconstructive Services

Growth hormone deficiency is associated with a variety of metabolic abnormalities, 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.  Because these abnormalities are thought to result in 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 medically necessary.

In children and adolescents, growth hormone is commonly used to treat short stature that is anticipated to result in an adult height that represents a significant variation from normal.  A significant variation from normal height is defined in this document as a height less than or equal to 2.5 standard deviations (SD) below the mean.  The short stature may be associated with GHD (idiopathic GHD, Prader-Willi syndrome) or normal GH levels (Turner syndrome, small for gestational age, idiopathic short stature).  While the use of GH therapy is associated with an increase in height, the use of growth hormone to enhance height is not considered medically necessary since there is no functional impairment associated with short stature, and no target height that can differentiate the presence or absence of a functional impairment.  However, the use of GH to address anticipated height which represents a significant variation from normal can be reconstructive when the cause of the reduced height is related to accidental injury, disease, trauma, treatment of a disease or congenital defect.  When there is no underlying accidental injury, disease, trauma, treatment of a disease or congenital defect, the use of GH in individuals whose height is expected to be a significant variation from normal is considered not medically necessary.  An example of a use which is not related to accidental injury, disease, trauma, treatment of a disease or congenital defect is idiopathic short stature.

In July 2003, Humatrope received FDA approval for use in non-GHD short stature (defined in the Humatrope product insert as more than 2.25 SD below the mean).  This approval was based on clinical trial data indicating that statistically significant height gains resulted from GH treatment in children with short stature absent other significant health conditions.  The data did not address the clinical significance of such gains in height or provide insight into potential long-term safety concerns which could arise when treating otherwise normal children with GH.  In normal healthy individuals with short stature alone (i.e. idiopathic- there is an absence of accidental injury, disease, trauma, or treatment of a disease or congenital defect), short stature itself has not been shown to result in disease, functional limitation, or psychological dysfunction.  The available evidence addressing the use of GH treatment in normal, healthy individuals with significant height variation from normal has not been shown to provide any significant benefits in physical function, health outcomes, or psychological status.  On the contrary, the use of GH in this population has been hypothesized to accelerate pubertal growth and advance bone age, shortening the period of growth during puberty.  Furthermore, the FDA released a statement highlighting recent evidence which suggested that individuals with certain kinds of short stature (idiopathic growth hormone deficiency and idiopathic or gestational short stature) treated with recombinant human growth hormone during childhood were at a small increased risk of death when compared to individuals in the general population (the Santé Adulte GH Enfant [SAGhE] study; Sävendahl 2012).  Aside from this study, there is very little data evaluating the long-term outcomes in short statured but otherwise healthy individuals.  Some experts have voiced significant concern with regard to possible increases in malignancy and other disease conditions in these individuals.  Until such time that questions regarding functional, psychological, and health benefits as well as the risks of GH treatment in normal healthy individuals with short stature alone in the absence of accidental injury, disease, trauma, or treatment of a disease or congenital defect are answered, use of this treatment should be limited. 

Furthermore, in 2014 a group led by Poidvin published the results of a study investigating the risk of stoke using data from a registry of French children treated with GH.  The study included data from 6874 subjects who received treatment with recombinant GH (rhGH) and are considered to have a low risk of mortality or morbidity. The study population was further stratified to look at two separate populations; 4600 subjects with isolated GHD and 868 subjects with idiopathic short stature (ISS).  The authors reported that, when using data from stroke registries from Oxford and Dijon as a comparator, the risk of stroke was significantly higher among the study subjects treated with rhGH.  Furthermore, the excess risk of stroke was largely attributable to a significantly higher risk of hemorrhagic stroke, and particularly subarachnoid hemorrhage (crude standardized incidence ratio (SIR)=5.7 and 6.3, respectively, with reference to the Dijon and Oxford data).  All findings were highly consistent between the two reference populations.  These findings highlight that the use of GH potentially poses significant undetected risks, and that the use of rhGH should be considered carefully.

Advocates of GH therapy often cite the potential psychosocial impairments associated with short stature.  Review of the published and peer-reviewed medical literature reveals that there is inadequate data to determine whether height increases in children with extreme short stature are associated with 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 5th 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.

When to Consider GH Testing

GH testing should be considered when evaluating individuals who have signs or symptoms of GH deficiency, such as short stature and decreased growth velocity, or who have conditions which are known to be associated with deficient GH production or response.

Indications for Growth Hormone Therapy

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.  Provocative testing remains the standard of care to confirm a diagnosis of GHD, and is required to demonstrate medical necessity.  Currently available tests used to assess GHD have variable performance characteristics and it is accepted practice to conduct two tests to assure that the individual is actually GH deficient.  Documentation of GHD is also 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.

Prader-Willi Syndrome (PWS)

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 2 years and then randomized to receive 1 of 3 different GH doses (0.3 mg/m2d, 1.0 mg/m2d, and 1.5 mg/m2d) for another 2 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 (Siemensma, 2012).  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. 

Bakker (2013) describes a longitudinal study of 60 children with PWS treated with GH and followed for 8 years.  The authors reported significant and sustained benefits from GH treatment with regard to lean body mass (p<0.001) and BMI standard deviation score (p<0.0001).  Height and head circumference had completely normalized.  IGF-1 standard deviation score increased +2.36 during the first year of treatment (p<0.0001) and remained stable through the rest of the study period.  No adverse effects due to GH treatment on glucose homeostasis, serum lipids, blood pressure, and bone maturation were reported.

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 (SD) 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 four 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/week, 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 (Am Acad Ped, 1997; Sandberg, 1994).

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 (Pasquino, 2000; Saggese, 1995; Tanaka, 1999).

Turner Syndrome

Short stature is almost universal in Turner syndrome (TS).  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 (RCTs) 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). 

Juloski and others reported the results of a blinded retrospective controlled study of 26 subjects with Turner syndrome to assess the impact of GH therapy on craniofacial morphology (2017).  Experimental group subjects had received GH treatment for a minimum of 2 years; controls were untreated with GH.  Cephalometric analysis was done for all subjects using lateral radiographs.  The authors reported that the anterior and total cranial base length was significantly larger in the experimental group vs. controls (p<0.001 and p<0.05, respectively).  No difference was observed in posterior cranial base length.  Measurements of the sagittal position of the maxilla did not differ significantly between groups, while vertical position showed significant difference (p<0.05).  The length of the maxilla was significantly larger in the experimental group (p<0.001).  Measurements of the mandible did not result in a statistically significant difference neither in sagittal or in vertical position.  The mandibular base length, mandibular ramus height and total mandibular length were significantly larger in the experimental group (p<0.05, p<0.001, p<0.001, respectively).  Both posterior and anterior face heights were considerably larger in the experimental group (p<0.001).  However, posterior-anterior face height index and the sum of posterior angles (Björk) did not differ significantly between groups.  They concluded, “Long-term growth hormone therapy has positive influence on craniofacial development in Turner syndrome patients, with the greatest impact on posterior facial height and mandibular ramus.  However, it could not compensate X chromosome deficiency and normalize craniofacial features.”

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 GH in short children post-transplant, although encouraging, is still short-term, and concern regarding an increased rate of graft rejection in certain populations remains.

Al-Uzri (2013) reported on a prospective, longitudinal observational study involving 483 children with chronic kidney disease followed for 2 years.  Multivariate modeling revealed that a significant association existed between catch-up growth and GH as measured on parent–proxy reports of child physical functioning (p<0.05) and social functioning (p<0.05).  Older children (15-17 years old) reported significantly higher ratings than their parents on the Pediatric Quality of Life Inventory Physical, Emotional, Social, and School Functioning scales compared with younger children (8-14 years old).

A study by Bizzarri (2017) investigated the final height in a cohort of 68 children with chronic kidney disease and growth deceleration, compared to 92 healthy control subjects.  The mean duration of GH treatment was 4.2 years.  At baseline the experimental group subjects had a height standard deviation score (SDS) -2.00 ± 1.02 vs. -0.96 in the control group (p<0.001).  Final height SDS was -1.25 ± 1.06 in GH group and -1.06 ± 1.17 in controls (p=0.29). Target adjusted final height SDS was -0.91 ± 1.03 in GH group subjects and -0.61 ± 1.17 in controls (p=0.1).  The authors reported that “Long-term rhGH therapy is able to reduce the linear growth deceleration of children with CKD, and ultimately to improve their final height, reducing the difference with target height.”

Children with Short Stature Homeobox (SHOX) Gene

GH treatment for children with SHOX gene is an FDA approved indication and has become a widely accepted therapeutic intervention.  

Blum (2013) published a report on a prospective, open-label, randomized study evaluating the long-term efficacy of GH treatment in short children with SHOX deficiency.  They also compared the final height of subjects with SHOX deficiency vs. those with TS.  The study consisted of a 2-year controlled study period with a subsequent extension period to final height.  Subjects were assigned to 1 of 3 groups: (1) subjects with SHOX deficiency who were untreated during the control period, and then GH-treated during the extension period (SHOX-D-C/GH group, n=25), (2) subjects with SHOX deficiency treated with GH during both periods (SHOXD-GH/GH group, n=27), and (3) subjects with TS treated with GH during both study periods (Turner-GH/GH, n=26).  There was significant loss to follow-up, with only 12 of 25 subjects in the SHOX-D-C/GH group completing the study to final height (48%), 16 of 25 the SHOXD-GH/GH subjects (59.3%) and 19 of 26 TS subjects (23.1%) completing to final height.  The authors reported that height standard deviation (SD) score gain from start of GH treatment to final height was similar between the combined SHOX-deficient groups and the Turner group.  In the final height population, 57% of the subjects with SHOX deficiency and 32% of the subjects with TS achieved a final height greater than -2 SD score.  The authors concluded that GH treatment in short children with SHOX deficiency showed similar long-term efficacy as seen in girls with TS. 

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 RCT 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 25th 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 25th 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 not medically necessary due to the minimal published data.

In 2015, the Pediatric Endocrine Society (Raman, 2015) published a report titled Risk of Neoplasia in Pediatric Patients Receiving Growth Hormone Therapy.  In this document they conclude:

In children without known risk factors for malignancy, GH therapy can be safely administered without concerns about an increased risk for neoplasia. GH use in children with medical diagnoses predisposing them to the development of malignancies should be critically analyzed on an individual basis, and if chosen, appropriate surveillance for malignancies should be undertaken. GH can be used to treat GH-deficient childhood cancer survivors who are in remission with the understanding that GH therapy may increase their risk for second neoplasms.

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 (Am Acad Clin Endocrinologists, 2009; Biller, 2002; The Endocrine Society [Molitch, 2011]), which offered the following observations and conclusions:

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.

Severe Burns

A literature review for the use of human growth hormone for the treatment of burns found nine published studies (eight RCTs, one case series).  Only one of the RCTs 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, three involved pediatric ICU subjects and two involved pediatric subjects treated with GH for 1 year post-release from the hospital.  The results are mixed with six 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 use of GH for the treatment of burn subjects is not considered effective. 

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, amyotrophic lateral sclerosis, and juvenile idiopathic arthritis (Adamopoulos, 2003; Albert, 2004; Bechtold, 2003; Darmaun, 2004; Sacca, 2012; Schibler, 2003; Stalvey, 2012).  No RCTs were identified to sufficiently demonstrate the appropriateness of GH therapy in these conditions and such use is not in accordance with generally accepted standards.

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.


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 3-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): GH is available as an artificially produced version of the natural hormone (also known 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 term which means “no known cause.”

Pituitary hormones: Hormones created by the pituitary gland, which include the following:

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*








Sparse, lightly pigmented, straight, medial border of labia

Breast and papilla elevated as small mound; diameter of areola increased


Darker, beginning to curl, increased amount

Breast and areola enlarged, no contour separation


Coarse, curly, abundant, but less than in adult

Areola and papilla form secondary mound


Adult feminine triangle, spread to medial surface of thighs

Mature, nipple projects, areola part of general breast contour

Classification of Sex Maturity States in Boys*










Scanty, long, slightly pigmented

Minimal change/enlargement

Enlarged scrotum, pink, texture altered


Darker, starting to curl, small amount




Resembles adult type, but less quantity; coarse, curly

Larger; glans and breadth increase in size

Larger, scrotum dark


Adult distribution, spread to medial surface of thighs

Adult size

Adult size

*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 3rd percentile of height for their age and gender.


Peer Reviewed Publications:

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  21. 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.
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  47. Saccà F, Quarantelli M, Rinaldi C, et al. A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results. J Neurol. 2012; 259(1):132-138.
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  53. 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.
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Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Association of Clinical Endocrinologists (AACE) Position statement growth hormone usage in short children. December 2003. Available at: Accessed on January 23, 2019.
  2. 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.
  3. Breederveld RS, Tuinebreijer WE. Recombinant human growth hormone for treating burns and donor sites. Cochrane Database Syst Rev. 2014;(9):CD008990.
  4. Cohen P, Rogol AD, Deal CL, et al.; 2007 ISS Consensus Workshop participants. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab. 2008; 93(11):4210-4217.
  5. 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. Endocr Pract. 2009; 15(Suppl 2):1-29.
  6. Duffy JMN, Ahmad G, Mohiyiddeen L, et al. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev. 2010;(1):CD000099.
  7. Fleseriu M, Hashim IA, Karavitaki N, et al. Hormonal replacement in hypopituitarism in adults: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016; 101(11):3888-3921.
  8. Genotropin®, [Product information], Rijksweg, Belgium. Pfizer Manufacturing Belgium NV. December, 2018 Available at: . Accessed on January 23, 2019.
  9. Grimberg A, DiVall SA, Polychronakos C, et al.: Drug and Therapeutics Committee and Ethics Committee of the Pediatric Endocrine Society Guidelines for Growth Hormone and Insulin-like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-like Growth Factor-I Deficiency. 2016. Available at: Accessed on January 23, 2019.
  10. Hodson EM, Willis NS, Craig JC. Growth hormone for children with chronic kidney disease. Cochrane Database Syst Rev. 2012;(2):CD003264.
  11. Humatrope, [Product information] Indianapolis, Indiana. Eli Lilly and Company. December, 2012. Available at: Accessed on January 23, 2019.
  12. Molitch ME, Clemmons DR, Malozowski S, et al.; Endocrine Society. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jun; 96(6):1587-1609.
  13. Ngim CF1, Lai NM, Hong JY, Tan SL, et al. Growth hormone therapy for people with thalassaemia. Cochrane Database Syst Rev. 2017; 9:CD012284.
  14. Norditropin® [Product information], Princeton, NJ. Novo Nordisk Inc. August 2017. Available at: Accessed on January 23, 2019.
  15. Nutropin®, [Product information], South San Francisco, CA. Genentech, Inc. December, 2016. Available at: Accessed on January 23, 2019.
  16. Omnitrope®, [Product information], Princeton, NJ. Sandoz GmbH. December, 2016. Available at: f. Accessed on January 23, 2019.
  17. Raman S, Grimberg A, Waguespack SG, et al. Risk of neoplasia in pediatric patients receiving growth hormone therapy--a report From the Pediatric Endocrine Society Drug and Therapeutics Committee. J Clin Endocrinol Metab. 2015; 100(6):2192-2203.
  18. Saizen® [Product information], Rockland, MD. Serono Inc. May, 2018. Available at: Accessed on January 23, 2019.
  19. Serostim® [Product information], Serono, Inc., Randolph, MA. May, 2017. Available at: Accessed on December 3, 2018.
  20. Thaker V, Haagensen AL, Carter B, et al. Recombinant growth hormone therapy for cystic fibrosis in children and young adults. Cochrane Database Syst Rev. 2015;(6):CD008901.
  21. Tanner JM. Growth at Adolescence, 2nd ed. Oxford, England, Blackwell Scientific Publications, 1962. SMR, sexual maturity rating.
  22. U.S. Federal Food and Drug Administration. Recombinant Human Growth Hormone (somatropin): Ongoing safety review - possible increased risk of death. Updated 08/04/2017. Available at: Accessed on January 23, 2019.
  23. U.S. Federal Food, Drug and Cosmetic Act, Sec. 301. [21 U.S.C. §333(e)]. Available at: Accessed on January 23, 2019.
  24. Wales PW, Nasr A, de Silva N, Yamada J. Human growth hormone and glutamine for patients with short bowel syndrome. Cochrane Database Syst Rev. 2010;(6):CD006321.
  25. Zomacton® [Product information], Ferring Pharmaceuticals Inc., Parsippany, NJ. July, 2018. Available at: Accessed on January 23, 2019.
Websites for Additional Information
  1. Centers for Disease Control and Prevention (CDC) National Center for Health Statistics. CDC Growth Charts United States. Available at: Accessed on January 23, 2019.

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.







Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Rationale and References sections.



MPTAC review. Initial document development. Moved content of DRUG.00009 Growth Hormone to new clinical utilization management guideline document with the same title.