THERAPEUTICS

Current Status of Growth Hormones Therapy in Pediatric Practice

Growth hormone (GH) is a polypeptide hormone, secreted by somatotropic cells of the anterior part of the hypophysis. Its application in therapy, first limited to growth hormone deficient children, has now been widened to various other clinical conditions, not necessarily related to short stature. Clinical trials conducted in recent years have proved the safety of its administration in both children and adults. The efficacy of this form of therapy varies, according to different authors, from enthusiastic data to very critical opinions. For many pediatric diseases, such as Turner syndrome, many experts regard growth hormone as the first-line treatment despite the high costs of the therapy. Mounting evidence suggests that growth hormone is safe and effective also in children with chronic renal failure and cystic fibrosis. Recently, consensus has been reached on the use of growth hormone in the children who are born small for gestational age and fail to catch-up in growth. This article summarizes the current data on growth hormone administration in modern pharmacotherapy.

Use in Growth Hormone deficiency

After excluding other diseases related to short stature and performing growth hormone stmulation tests, in which, if the induced growth hormone peak does not exceed 10 IU/L, growth hormone deficiency is diagnosed (1). This definition of growth hormone deficiency has been criticized by many authorities, as clinical trials have shown poor reproducibility and high false-positivity rate. However, the above mentioned definition comtinues to be used. These patients are at the lowest risk for adverse effects and receive the greatest benefit. Still, costs of treatment in terms of money, effort, and perhaps quality of life, are substantial.

Dose: Recommended doses vary, but most experts suggest 0.17-0.3 mg/ kg/ week (0.35-0.85 IU/kg/week), divided into 6 or 7 daily doses injected subcutaneously at bedtime. . Dose is adjusted every 3-4 months.

Response: Growth of the deficient child is accelerated within months (In fact, the therapy is discontinued if the gain in length was less than 1 cm in first 6 months of therapy) . Other benefits, such as increased strength, progress in motor development, and reduction of body fat are also noticed. Most children achieve their adult final height within a normal, midpparental-adjusted range. The results are best in patients with severe deficiency in whom predicted final height is very low. Assessing the psychological value of treatment is difficult but most children and families are enthusiastic once the physical benefits begin to be seen.

Duration of therapy: The optimal duration of therapy is still debatable. Till recently, the therapy was recommended till final adult height was achieved. A randomized trial recently demonstrated that growth hormone response to stimuli normalizes spontaneously with time, especially during puberty and GH therapy can be safely withdrawn at this stage (2, 3). However, withdrawl of  GH cal lead to increased viceral adipose tissue, decreased lean body mass and altered lipid profile within 12-24 months. Thus, many authors (2, 4, 5) recommend lifelong GH therapy. Thus, the withdrawl of GH therapy should be individualised, taking into account the cost-risk-benefit analysis.

Use in other forms of Short Stature

Many conditions besides GH deficiency cause poor growth. A large body of data on efficacy and safety of growth hormone (GH) treatment for various non-growth hormone-deficient (GHD) growth disorders has accumulated from a combination of clinical trial and post-marketing sources in the last 20 years or so. GH therapy has been shown to improve short-term growth in many conditions, but long-term height gains are usually poorer than those achieved when GH deficiency is the cause of shortness. Higher ("pharmacologic") doses are typically required to achieve efficacy; side effects are more common (than in case of GHD) and vary according to the condition being treated.
The current recommendations are:

Turner Syndrome

Turner Syndrome, though associated with short stature does not have deficiency of growth hormone or growth hormone-Insulin like growth factor-I (GH-IGF-1) axis abnormality. Still they respond to GH therapy and it is cosidered as a standard of care in these patients.

Dose: The dose recommended is 0.375 mg/kg/week divided in 7 divided doses. The dose is individualized according to the growth response and IGF-1 level (6).

Response: The response appears to be dose dependent (7).  Median gain in adult height reported is 5-7.5 cm. A recent Cochrane Study (8) concluded, “Recombinant human growth hormone (rhGH) doses between 0.3 to 0.375 mg/kg/wk increase short-term growth in girls with Turner syndrome by approximately three (two) cm in the first (second) year of treatment. Treatment in one trial increased final height by approximately six cm over an untreated control group. Despite this increase, the final height of treated women was still outside the normal range.” The optimal age of initiation of therapy is yet to be determined; but most experts recommend that therapy should be initiated as soon as growth failure is detected. High mid-parental height, longer duration of therapy and higher growth velocity in first year of therapy are associated with better outcome. Proper sex hormone replacement therapy further enhances final adult height. These patients have low bone mineral density (BMD) and the growth hormone therapy is supposed to improve this. However, recent studies failed to confirm this (9, 10).

Noonan syndrome
Because of its similarity to turner syndrome and GH/IGF-1 axis abnormalities, growth hormone therapy is supposed to be beneficial in this condition also. However, concrete data in the form of large randomised trials is lacking (11). All patients with Noonan syndrome do not respond to GH therapy. Recently discovered mutation in PTPN 11 gene might be at least partially responsible for this (12).

Chronic Renal Failure (CRF)
Growth failure is a prominent feature of CRF in young children. Even though GH level is increased in these children due to decreased renal clearance of the hormone, the GH/IGF-1 axis is disturbed because of decrease in GH receptors and increased level of IGF-1 binding proteins 1 and 3. Thus, growth failure in CRF is responsive to GH therapy.

Dose: Dose recommended is 0.35 mg/kg /week.

Response:  GH therapy leads to quick catch-up growth; a recent Cochrane review concluded that rhGH therapy in children with chronic kidney disease resulted in a 3.80 cm/y increase in height velocity above that of untreated patients (13). The response depends on the dose (5) and degree of renal function derangement at the initiation of therapy (14). That is why it is now recommended that GH treatment in these children should be started as soon as growth failure is detected (15). Interestingly, GH therapy in these patients does not accelerate the process of puberty in these patients as in those with GH deficiency or idiopathic short stature (16). Since puberty is delayed in these patients, it is presumed that with optimal GH therapy, patients can achieve normal final height; the authors of the Cochrane Review (13) recommend long term trials to prove this assumption. Unfortunately, the growth failure in CRF persists even after renal transplantation. Though there is some data which suggest that the use of recombinant human growth hormone might efficaciously improve growth velocity in the persistently growth-retarded allograft recipient (17), more evidence is needed to recommend continuation of GH therapy even after transplantation.

Short children born Small for Gestational age (SGA)
SGA is defined as birth weight and/or length two standard deviations below the mean for gender and gestational age. Most of these infants have post-natal growth acceleration (catch-up) and by 2 years of age, 90% of these achieve normal height for age. The rest, who fail to do so, are the candidates for GH therapy. Recently, consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society (18) also recommended use of GH in these patients.

Dose: Starting dose should be in the range 35–70 µg/kg/d, with the higher doses used in those with the most marked growth retardation (18).

Response: Factors associated with the response to GH over the first 2–3 yr include age and height SD score (SDS) at start of treatment, mid-parental height, and dose. Average height gains after 3 yr of GH treatment range from 1.2–2.0 SD for doses of 35–70 µg/kg/d. After the initial catch-up, most of this height gain is maintained up to adult height. The maintenance phase of GH treatment seems to be less dose dependent (19). Children with a recognized syndrome respond less well to GH than those with non-syndromic SGA (19). There should be a positive response to GH treatment (height velocity SDS more than +0.5 in the first year of treatment). If there is an inadequate response, reevaluation is indicated, including consideration of compliance, GH dose, diagnosis, and the decision to discontinue treatment. In those with a positive response to GH, withdrawal of GH therapy after 2–3 yr leads to catch-down growth and is not recommended (19). Discontinuation of GH treatment in adolescence is recommended when the growth rate falls to less than 2 cm/yr. It is currently unknown whether GH therapy for the SGA subject through childhood and adolescence is associated with benefits or amplification of metabolic complications (glucose intolerance, altered lipid profile, etc.)  of SGA.
A recent study (20) has suggested that the same recommendations may be true even for very preterm babies, but appropriate for gestational age and who do not show adequate catch-up growth.

Prader-Willi Syndrome (PWS)
The use of GH therapy in treatment of patients with PWS has been licensed by the US-FDA since 2000.

Dose: The standard dose in these patients is 0.24 mg/kg/week, based on ideal body weight (21).

Response: Use of GH in these patients not only improves growth velocity, but also lean body mass, body composition, muscle strength, mobility, lipid profile, behavioral problems and quality of life (22, 23). Recently, there were reports of death of patients of PWS soon after initiation of GH therapy (24). Concerns for an increased mortality in PWS children starting GH therapy led to a call for cessation of its use. Children with PWS are at risk of developing SDB secondary to both deficient autonomic sleep control and upper airway obstruction (UAO). It has been suggested that GH exacerbates pre-existing gas-exchange deficiencies in three ways: (a) by stimulation of adenotonsillar hypertrophy; (b) by a rise in basal metabolic rate with a resultant rise in oxygen demand; and (c) by normalization of previously decreased hydration with augmentation of volume load (22). Thus, a subset of PWS patients are at risk during this window of vulnerability shortly after initiation of GH. Considering benefits of GH in these patients on one hand and the fact that it is difficult to predict who will worsen with GH, patients with PWS should have polysomnography before and after starting GH and should be monitored for sleep apnea with upper respiratory tract infections (21). In case, the patient develops any sign of upper airway obstruction or any new onset sleep apnea, the treatment should be terminated (21). The respiratory infections in these patients should be promptly diagnosed and aggressively managed.

Idiopathic Short Stature (ISS)
Children with short stature but no hormonal deficiency or systemic illness are grouped under the term, idiopathic short stature. Being a heterogeneous group, only a subset of these patients respond to GH therapy, given in high dose.

Dose:  The dose in this condition is not standardized; often “high doses” are needed.

Response: Although some large studies have  shown that GH therapy in this condition results in rapid catch up growth (25), there are number of studies with conflicting results (26). A recent Cochrane review (27) also concluded that GH therapy can increase short-term growth and improve (near) final height. Increases in height are such that treated individuals remain relatively short when compared with peers of normal stature. The authors of this review recommended that large, multicenter RCTs are required which should focus on final height and address quality of life and cost issues.

Cystic Fibrosis
Children with cystic fibrosis (CF) have problems with poor linear growth and inadequate weight gain. Nutritional augmentation has been the mainstay of therapy for improving both weight and height in CF; however, inadequate growth continues to be a problem. Furthermore, protein catabolism has been documented even in non-acutely ill adults and children with CF, and could adversely affect longitudinal growth. Human recombinant GH has positive effects on nitrogen balance, and multiple studies have demonstrated improved height and weight in children treated with GH (28). Several reports suggest that GH treatment results in improved forced vital capacity, and multiple studies have found improved clinical status as measured by decreased hospitalizations and courses of intravenous antibiotics. Furthermore studies to date also suggest that GH results in improvement in exercise tolerance and bone accumulation. To date significant side effects, including glucose intolerance, have not been reported (28, 29, 30).

Experimental (“Off-label”) use in Other forms of Short Stature
There are anecdotal reports of use of GH therapy various other forms of short stature, like cerebral palsy, X-linked Hypophosphatemic rickets, corticosteroid-induced growth failure, bone dysplasia, inflammatory bowel disease, celiac disease, etc.

Experimental (“Off-label”) use for Benefits beyond height
GH has occasionally been used for other purposes than accelerating growth or replacing deficiency. Nearly every hormone available for administration has been given to non-deficient people in hope of obtaining improvement for various conditions for which other treatments are unsatisfactory. With a few exceptions, benefits are modest and side effect risk is higher. Experience with GH has yielded the same results. A wide array of clinical conditions are included in this category, e.g., HIV/AIDS (31, 32, 33), burns (34),  juvinile idiopathic arthritis (35), etc. Out of these, probably we have maximum data on HIV/AIDS and this preliminary data is encouraging.

Contraindications to Growth Hormone therapy

The growth hormone therapy is contraindicated (36):

Adverse Effects of Growth Hormone Therapy
The advere effects are listed in table-1

Table-1. Adverse effects of growth hormone therapy (36)

Conclusion
Growth Hormone therapy, first limited to growth hormone deficient children, has now been widened to various other clinical conditions, not necessarily related to short stature. In some clinical conditions, like Turner Syndrome, chronic renal failure and short children born small for gestational age, growth hormone therapy is considered as a standard of care. Besides, US-FDA has approved it for use in children with Prader-Willi Syndrome and idiopathic short stature. There is mounting evidence that suggests that human recombinant growth hormone provides safe and effective therapy in children with cystic fibrosis. The results are encouraging for use in HIV/AIDS also. In addition, there have been attempts for using this therapy in a wide array of clinical conditions, like cerebral palsy, X-linked Hypophosphatemic rickets, corticosteroid-induced growth failure, bone dysplasia, inflammatory bowel disease, celiac disease, burns and juvinile idiopathic arthritis, etc.

           
-Puneet Kumar, New Delhi