This is a summary of the highlights of this report dealing with the recommendations for clinical use of growth hormone.  Growth Hormone (GH) has been used to treat children with growth hormone deficiency for more than 40 years.  In 1985, pituitary-derived GH was linked to contaminated prions for the development of Creutzfeldt-Jakob disease, leading to discontinuation of this product.  Biosynthetic GH became available and human GH of recombinant DNA origin was produced commercially and is has been available and approved for use in this country.  There are 7 products manufactured by 5 different companies approved for treatment in the United States, both in children as well as in adults.  In the United States there are approximately 50,000 adults who have GH deficiency and 6,000 new cases of GH deficiency are being diagnosed each year. 

Growth Hormone Therapy in Adults

• The usefulness of GH treatment in adult who have completed their statural growth derives from the role of GH in the following processes:

• Increasing bone-density and lean tissue, and enhancing exercise capacity.

• Bolstering cardiac contractility and decreasing adipose tissue.

• Improving mood and motivation.

Although evidence suggests that GH deficient adult patients are susceptible to the development of premature cardiovascular disease, few data are available to demonstrate the ability of growth hormone treatment to change cardiovascular mortality.

In August of 1996 the FDA approved GH for use in adult patients with GH deficiency.  Adults selected for GH therapy should have an easily recognized cause, such as pituitary disease (including tumors or surgical damage), hypothalamic disease following irradiation, trauma, and reconfirmed childhood GH deficiency.  Such patients clearly have GH deficiency and would most likely benefit from GH replacement therapy.  Other indications for GH therapy in adults have not been approved by the FDA to date.  Prescribing GH for off-label indications is a matter of major concern.

The laboratory diagnosis of GH deficiency in adults is determined by dynamic endocrine testing.  Numerous stimulation tests are available - none perfectly predicts GHD or has 100% sensitivity or specificity.  A peak value of less than 5µg/L after insulin stimulation is considered the gold standard.  Arginine and growth hormone-releasing hormone (GHRH) can be used and may be more acceptable than arginine alone or L-dopa alone.  Serum IGF-1 concentrations are useful indicators of GH adequacy.  However, a normal serum IGF-1 level in adults does not exclude the presence of GH deficiency.  For the patient with a childhood-onset of GH deficiency the decision to reinitiate therapy should not rely simply on IGF-1 measurements to reconfirm the diagnosis of GH deficiency in adults; a provocative test is recommended.

Adults with GH deficiency are more susceptible than children to the side effects of GH. Therefore, GH therapy should be titrated with a low dose of 0.1, slowly reaching the maximum of 0.3 mg/day.  The goal of replacement is to minimize symptoms (for example, fatigue, poor endurance and sense of well-being) and improve the quality of life. Achieving a serum IGF-1 concentration of normal range for age and sex might be accomplished. The end point for GH replacement in adults has been linked to bringing IGF-1 levels into the normal range. This is usually associated with improvement in blood lipid levels, waist-to-hip ratios, body composition and quality of life, and hopefully leading to a reduction of cardiovascular disease.

GH therapy is contraindicated in any patient with HIV or AIDS, those with a malignant lesion, as well as those with pseudotumor cerebri or proliferative diabetic retinopathy.  Diabetes mellitus is not a contraindication, however GH therapy might impede the control of type 2 diabetes.  Pregnancy is not an absolute contraindication, but GH therapy during pregnancy in women with GH deficiency is not approved by the FDA.

Patients who complete GH therapy for childhood-onset GH deficiency are in a special category.  A resting period of treatment with GH is recommended, although no precise interval before restarting GH treatment has been established.  For those patients with structural disease such as craniopharyngioma, there is less doubt about whether GHD persists and therefore need for treatment; nonetheless there are less stringent criteria for idiopathic GH deficiency.  In the latter patients, hypothalamic-pituitary function might have matured and GH deficiency might become normal for adults, therefore not requiring GH treatment.  Starting dosages of 0.4 to 0.8 mg/day are suggested with gradual increments over the next 4 to 6 weeks.  The doses required for these types of patients might be higher than those required for adults with GH deficiency. 

GH Therapy in Children

FDA approved indications for GH treatment in children include:

• Growth hormone deficiency

• Turner syndrome

• Chronic renal insufficiency

• Small for gestational age or intrauterine growth retardation

• Prader-Willi syndrome

• Continued height deficit at puberty

GH deficiency may result from abnormalities in the hypothalamus and less frequently from pathologic pituitary conditions, i.e. tumors.  There are some genetic causes which include abnormality in the GH gene, in the Pit-1 gene or POU1F1 gene that regulates development of the pituitary cells secreting GH.  The evaluation of GH deficiency in a short child should not be initiated until other causes of growth failure such as hypothyroidism, chronic ischemic disease, Turner syndrome or skeletal disorders have been ruled out.  The key facts in the history and physical examination for possible GH deficiency include:

• The neonate with hypoglycemia, prolonged jaundice, microphallus, or traumatic delivery.

• Patient with cranial irradiation

• Head trauma or CNS infections

• Consanguinity or an affected family member

• Craniofacial midline abnormalities

• However, short stature might be the only feature present.

Candidates for treatment are: patients with a height deficit of more than 1.5 SD below the midparental height, height more than 2 SD below the mean, and a 1 year height velocity more than 1 SD below the mean for chronological age.  In the absence of short stature, a 1-year height history of more than 2 SD below the mean might be sufficient to investigate the patient.  Of course if there are signs of intracranial lesion or other hormonal deficiencies or neonatal symptoms and signs of GH deficiency the patient should be assessed for GH status.  With increasing use of magnetic resonance imaging, abnormalities in the hypothalamic-pituitary region may be detected.  For evaluation of the genetic disorders, patients with early onset of growth failure should have genetic mutations studied.  Unfortunately, these are only available in research laboratories. 

GH provocation tests for the diagnosis of GH deficiency include arginine, clonidine, glucagon, insulin and L-dopa. These should be performed in a child whose clinical data meets the criteria for GH deficiency. A peak concentration below 10 µg/L has traditionally been the level to support the diagnosis.  Nonetheless, it should be kept in mind that overlap could exist in peak GH concentrations between normal children and those with GH deficiency. Steroid priming in the immediate peripubertal period might be necessary, but no consensus exists on the use of sex steroids before provocation tests.   IGF-1 and IGFBP-3 should be monitored, keeping in mind that there might be overlap with the normal values.  It’s important to reiteate that the clinician must integrate all available data (clinical, auxologic, radiologic, and biochemical) before making the diagnosis of GH deficiency. Monitoring growth progression in these patients is most important, both before and during treatment.

In the neonate with hypoglycemia GH should be tested.  A random level of less than 20 ng/mL is significant.  Growth hormone testing should not be done while the patient is hypothyroid.

Treatment recommendations in children with childhood-onset GH deficiency usually begin with a dose of 0.3 mg/kg per week, divided into daily or 6-times-per-week.  Depot preparations of GH are also available.  The optimal dose and timing of administration of these preparations are being investigated in childhood. Treatment is continued until final height or epiphyseal closure has been documented.

In all girls with short stature or unexplained failure to thrive, a karyotype should be performed to rule out Turner syndrome.  In girls with this syndrome height should be plotted on specific Turner syndrome growth charts.  GH has been shown to accelerate growth in girls with Turner syndrome resulting in increased final height.  Evidence also exists that dosages higher than those currently recommended produce a greater increase in final height without an apparent increase in adverse events. Future GH therapy for such patients should be considered when the height is below the 5^th percentile of a normal growth curve for girls.  For girls younger than 9 years of age, therapy can be initiated with GH  at a dose of 0.05 mg/kg per day (0.15 IU/kg per day).  Anabolic steroids should not be used alone for the promotion of growth and they should not be used above 0.05 mg/kg per day.  Current data indicate that estrogen has no role as a growth promoting agent, but the initiation of estrogen therapy should be timed so as to maximize any negative effect on growth and adult height while inducing puberty at an approximately normal age.

In children with chronic renal insufficiency, GH might be initiated after all other metabolic derangements are corrected.  GH treatment is recommended at a dose of 0.35 mg/kg per week, divided into 6 or 7 dosages.  Currently, GH is not recommended for post-transplantation patients, unless it is given as a part of a research study. 

For children with intrauterine growth retardation or small for gestational age, GH was approved by the FDA for those who did not catch up by 2 years of age.  The  recommended dose is 0.48 mg/kg per week, divided into daily dosages.  Although data on final height on such treated patients is not available yet, treatment should be continued until final height is achieved. 

For Prader-Willi patients, GH testing is not a requirement in using GH treatment.  In such patients there should be an appreciable acceleration of growth and a decreasing fat mass with a resultant increase in lean body mass.  Physical strength and agility might also improve.  Data also show substantial improvements in near-final adult height after GH treatment in these patients.  The FDA approved GH treatment for such patients at a dose of 0.24 mg/kg per week. 

Children with GH deficiency who still have an appreciable height deficit at puberty may benefit from increased dosing of GH during the pubertal growth spurt.  Data showed that doubling GH dosage during puberty to 0.7 mg/kg per week results in an increase of approximately 5 cm in near-final adult height, in comparison with results of treating pubertal GHD children with conventional dosages of 0.3 mg/kg per week. 

It should be kept in mind that there might be side effects of GH treatment such as edema, arthralgia, myalgia, paresthesias, and carpal tunnel syndrome.  Most of these symptoms commonly occur at the onset of therapy and resolve within one or two months of treatment. These are more frequent in adults than in children. Transient gynecomastia has also been described in children and adults during GH replacement therapy.  Pseudotumor cerebri might occur more frequently in children.  This usually resolves after GH replacement therapy is discontinued.  Only a few of these patients developed the same problem when GH is resumed.  Slipped capital femoral epiphysis may occur more frequently in children with GHD than in others.  Thus, any child receiving GH treatment with knee pain, hip pain or is limping should be carefully investigated.  Occasionally, lipoatrophy may also occur at the GH injection site.  Increased serum creatinine levels might be seen in patients with end-stage renal disease treated with GH.  In randomized ICU patients treated with GH, there was an increased mortality as compared to the placebo-treated patients.  Thus, at this time GH is not recommended for treatment of patients with acute catabolic conditions.  GH may induce transient resistance to insulin, however glucose intolerance may result less frequently.  The glycemia should be monitored periodically as well as glycosylated hemoglobin levels.  Pancreatitis has been reported in patients treated with GH although the precise cause for this complication is uncertain.  Reports have also linked GH to an increased incidence of leukemia; however subsequent studies have not confirmed such an increase.  GH therapy is contraindicated in patients with active malignant conditions, although it can be initiated in those who have had no malignancies for at least 5 years.  The GH Research Society recently reviewed this subject extensively and found no association of GH therapy with the promotion of other tumors.  

The committee recommended that GH therapy be best accomplished under the direct supervision of a clinical endocrinologist.

This is a very timely review which should be available and in the hands of every pediatric endocrinologist, as a good reference source. Additionally, the reader is referred to two interesting editorials on the subject: (1)  ML Vance. Can growth hormone prevent aging NEJM 348:779;2003 and (2) JF Drazen. Inappropriate advertisements of dietary supplements  NEJM 348:777:2003. 

Fima Lifshitz, MD