The principal objective of GH treatment in children with GH deficiency is to improve final adult height. Human pituitary-derived GH was first used in children with hypopituitarism over 50 years ago, and abruptly ceased in 1985, after the first cases of Creutzfeld-Jacob disease were recognized. Since 1986, recombinant human GH (rhGH) has been the exclusive form of growth hormone used to treat GH deficiency in the United States and most of the world.
Short stature without overt growth hormone deficiency is very well described, and occurs in Turner Syndrome, renal failure, malnutrition, cardiovascular disease, Prader-Willi syndrome, small for gestational age, inflammatory bowel disease and osteodystrophies-and clearly represents the majority of short/poorly growing children in the world. Although not the focus of this discussion, it is important to realize that-in clinical terms-GH therapy is used to treat growth failure, rather than a biochemical GH deficiency. GH therapy in this setting, in combination with disease-specific treatments, generally improves statural growth and final adult height.
The primary goals of the treatment of a child with GH deficiency are to achieve normal height during childhood and to attain normal adult height for children with GH deficiency. Children should be treated with an adequate dose of rhGH, with the dose tailored to that child’s specific condition. FDA guidelines for GH dosing varies according to the indication and are given in Table 2 (80).
Administration of rhGH in the evening is designed to mimic physiologic hGH secretion. Treatment is continued until final height or epiphyseal closure (or both) has been recorded. GH therapy, however, should be continued throughout adulthood in the case of GHD, to optimize the metabolic effects of GH and to achieve normal peak bone mass-albeit at significantly lower "adult" doses. Adult GH replacement should only be started after retesting the individual and again demonstrating a failure to reach the new age-appropriate GH threshold, if appropriate.
Table 2. GH dosage.
|
Indication |
Dose (mg/kg/wk) |
|---|---|
|
GH Deficiency Children Pre-pubertal Pubertal Adults |
0.16 - 0.35 0.16 - 0.70 0.04 - 0.175 |
|
Turner Syndrome |
0.375 |
|
Chronic renal insufficiency |
0.35 |
|
Prader-Willi Syndrome |
0.24 |
|
SGA |
0.48 |
|
Idiopathic short stature (ISS) |
0.3 – 0.37 |
The growth response to GH treatment is typically maximal in the first year of treatment and then gradually decreases over the subsequent years of treatment. First year growth response to rhGH is generally 200% of the pre-treatment velocity, and after several years, averages 150% of the baseline. Height improvements of 1 SD are typically achieved in children with GHD after two years of treatment, and between 2 and 2.5 SD after five or seven years. GH doses are often increased if catch-up growth is inadequate and/or to compensate for the waning effect of rhGH with time. It is critically important to maximize height with GH therapy before the onset of puberty. Several investigators have advocated modifying puberty or the production of estrogens by the use of GnRH super-analogues(5,6) and aromatase inhibitors (89-92), respectively, in order to expand the therapeutic window for GH treatment, especially in older males.
The response to GH may vary in children if they are not GH deficient (i.e, SGA, Turner syndrome). Recent reports indicating an association of the deletion of Exon 3 on GH receptor.
Children receiving GH therapy require periodic monitoring. Three-month intervals are commonly chosen to allow for sufficient growth for a meaningful measurement, while minimizing time between dose adjustments/intervention. During follow up visits, height, weight, pubertal status, inspection of injection sites, and a comprehensive clinical exam should be initiated. In clinical practice, there are several parameters to monitor the response to GH treatment; the determination of the growth response (i.e. change in growth velocity, ∆GV) being the most important parameter.
Table 3. Summary of follow-up evaluation.
|
Parameters |
Assessment |
|---|---|
|
Bone age |
12 month intervals to assess the predicted height. |
|
Thyroid Function Test |
6 month intervals, or immediately, if growth velocity decreases. |
|
Serum IGF1 and IGBP-3 |
3-12 month intervals. Most useful in maintaining GH dose in 'safe' region. They do not necessarily correlate with growth velocity. |
|
Metabolic panel, CBC,ESR, HbA1C |
12-month intervals. |
|
Dose adjustment |
Based on growth response, pubertal stage, IGF level and comparison to predicted height. |
|
Adverse Events |
Every visit. |
To date, multiple studies have demonstrated the safety of GH therapy(7-10). Patients, however, should be monitored closely during treatment. While rhGH treatment is generally considered safe, concerns have been raised about tumorigenicity of chronically elevated IGF1 levels. It would therefore seem prudent to maintain IGF1 levels in the mid-normal range for age/pubertal stage and gender. Although the long-term consequences of elevated IGF1 levels during childhood are not known, some investigators recommend that dose reductions be considered after the first two years of therapy if IGF1 levels continue to be above the normal range, (80).
Another concern is the use of GH in patients with Prader-Willi syndrome. A total of 22 fatalities have been reported in patients with Prader-Willi syndrome during or after rhGH therapy (93). Although there is no clear evidence that those deaths are related to GH therapy, it was postulated that GH/IGF-1 may worsen sleep apnea or hypoventilation via increasing tonsillar/adenoid tissue or worsen pre-existing impaired respiration by increasing volume load (94). However, studies on respiratory function of subjects with Prader-Willi syndrome during rhGH therapy have only demonstrated improved respiratory drive and function (95). In fact, a recent study showed that all subjects tested had abnormal sleep studies/parameters prior to initiating GH treatment, and that GH treatment resulted in an improvement in sleep apnea in the majority of patients with PWS. Importantly, however, a subset had worsening of sleep disturbance shortly after (6 wk) starting GH when also developing a respiratory infection (96). Because it is difficult to predict who will worsen with GH treatment, these authors recommend that patients with Prader-Willi syndrome have polysomnography before and 6 wk after starting rhGH and should be monitored for sleep apnea during upper respiratory tract infections. IGF-1 levels should also be monitored.
The common side effects of GH therapy are summarized in Table 4.
Table 4. Real and Theoretical Side Effects of GH treatment
|
Side effects |
Comment |
|---|---|
|
Slipped capital femoral epiphysis (SCFE) |
Unclear whether GH causes SCFE or if it is a result of diathesis and rapid growth, induced by the GH. Should be evaluated at each visit for knee or hip pain/limp |
|
Pseudotumor cerebri |
The mechanism is unclear, but it may be a result of GH induced salt and water retention within the CNS. Complaints of headache, nausea, dizziness, ataxia, or visual changes should be evaluated immediately |
|
Leukemia |
Numerous large studies have not shown any association between rhGH and leukemia in children without predisposing conditions(7,11) |
|
Insulin resistance |
Patients with a limited insulin reserve may develop glucose intolerance. HbA1c should be monitored |
|
Recurrence risk of CNS tumors |
Extensive studies did not support this possible side effect(12,13) |
|
Hypothyroidism |
Almost 25 % of children may develop declines in serum T4 levels, generally reflecting enhanced conversion of T4 to T3, rather than outright hypothyroidism |
|
Transient gynecomastia |
These are attributed to anabolic and metabolic effects of GH |
|
Scoliosis |
Follow for progression and refer as appropriate |
|
Sleep apnea/sleep disturbance |
GH treatment might worsen sleep apnea/sleep disturbance in patients with Prader-Willi Syndrome, especially during a concomitant respiratory infection. |
Recently, rhIGF-1 and rhIGF-1/rhIGFBP-3 became available for the treatment of primary IGF-1 deficiency resulting from abnormalities of the GH molecule (resulting in a bioinactive GH), the GH receptor (known as Laron syndrome) or GH signaling cascade (97). These compounds may be useful for other forms of GH insensitivity syndrome (an umbrella term for the combination of high endogenous GH levels with low IGF1 combined with short stature or other clinical evidence of GH deficiency) but are not yet approved for this indication and at present should only be used for patients unresponsive to rhGH therapy. Studies have shown that rhIGF-1 significantly improves height in children unresponsive to rhGH(98, 99), and clinical trials clearly demonstrated better response to IGF-1 therapy when initiated at an early age (100).
The recommended usual dose in children is 100-200 microgram/kg/day (101). The most common side effects of IGF-1 treatment are pain at injection site and headaches which mostly diminishes after first month of treatment (97). Other less common side effects are lipohypertrophy at the injection site, pseudotumor cerebri, facial nerve palsy and hypoglycemia (100). Another effect of IGF-1 treatment is a significant increase in fat mass and BMI (102)—in contradistinction to the lipolytic effect of rhGH treatment. Coarsening of facial feature and increased hair growth are other prominent side effects and most commonly are seen during puberty. Growth of lymphoid tissue is a concern which may require tonsillectomy (97).