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Recombinant growth hormone (rhGH) is used as a doping agent because of its predictable anabolic effects, (i.e., it increases the lean body mass and decreases fat, finally improving strength and power) [36]. Although it is not definitely proven that rhGH is effective in enhancing sport performance [37], its use in certain sports, especially in association with steroids, is widespread. The GH has been forbidden since 1989 by the International Olympic Committee. In the 2004 Olympic Games in Athens, a test for GH abuse was introduced, but no athlete was found positive despite the several hundreds of analyses being performed [38].
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Growth hormone
Recombinant growth hormone is approved for use in the UK by the National Institute for Health and Care Excellence for children with growth failure associated with a defined number of conditions, for example growth hormone deficiency. Growth hormone is not licensed in the UK for ISS, although it is in the United States of America. There are few studies reporting on the efficacy and safety of long term treatment with growth hormone in ISS.
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The availability of recombinant growth hormone has generally led to effective correction of growth insufficiency in children with multiple or IGHD due to pituitary developmental defects, but it is not always efficacious for some idiopathic short stature patients or for other problems associated with syndromic pituitary hormone deficiency (i.e. septo-optic dysplasia and other severe craniofacial abnormalities) (Bryant et al., 2007; Hintz, 2005; Zucchini, 2008; Zucchini et al., 2008; Cohen et al., 2008). Thus, treatment of children with pituitary hormone deficiency can be challenging, as well as expensive.
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Treatment
Both FSS and CDGP should be considered as normal variants. The purpose of differentiating between them is to aid prediction of final adult height and ongoing management.
Growth hormone
Recombinant growth hormone is approved for use in the UK by the National Institute for Health and Care Excellence for children with growth failure associated with a defined number of conditions, for example growth hormone deficiency. Growth hormone is not licensed in the UK for ISS, although it is in the United States of America. There are few studies reporting on the efficacy and safety of long term treatment with growth hormone in ISS.
Sex steroids
Constitutional delay in puberty may have a significant impact on the emotions and confidence of the young person. Referrals for assessment are more common in boys, partly explained by the normal physiology of puberty whereby girls start puberty at an earlier age. Boys are more vulnerable to teasing and bullying if they have short stature or are seen as having no pubertal progress. It is possible to offer oestrogens for girls at the age of 12 and testosterone for boys at 14 years to induce puberty in CDGP. Both are licensed for use and the British Society of Paediatric Endocrinology and Diabetes has guidelines available for pubertal induction. Doses are increased gradually to mimic physiological pubertal development. In our experience, boys who choose to have testosterone supplementation start to feel much more confident soon after starting supplements with an increase in their height velocity starting soon after.
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Growth Hormone
The use of recombinant growth hormone (rhGH) in pediatric renal transplant recipients significantly improves growth velocity and SDS.48,65,70,71,82 The NAPRTCS reports that growth velocity almost tripled 1 year after starting rhGH therapy, with a slight slowing after 2 and 3 years of therapy. There is some evidence to suggest that rhGH increases allogeneic immune responsiveness, leading occasionally to acute rejection and graft loss in addition to direct adverse effects on graft function.21,31,76,79 These adverse effects were not observed in the NAPRTCS data but were observed in earlier studies in high-risk patients (e.g., patients who had had prior acute rejection episodes or who were on alternate-day steroid therapy). Growth hormone therapy is generally started in prepubertal children at least 1 year after transplantation and continued until catch-up growth is achieved or until puberty ensues. We have found that cyclosporine levels may decrease after initiation of rhGH therapy; we follow drug levels closely, along with using adjunctive therapy, such as MMF, at appropriate doses.
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Growth Hormone
Use of recombinant GH (rhGH) in growth-retarded pediatric renal-allograft recipients results in impressive improvements in growth, without any increase in allogenic immune responsiveness.3 rhGH therapy is usually started in prepubertal children at least 1 year after transplantation, and continued until catch-up growth is achieved or until puberty ensues.
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Introduction
Recombinant human growth hormone (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children has been subject to considerable scrutiny. GH for replacement therapy until 1985 was extracted from cadaveric pituitary glands, but this was stopped in most countries that year, following the recognition that it could transmit Creutzfeldt–Jacob disease, with patients still being diagnosed after incubation periods up to 40 years [1]. The same year, rhGH was approved as a treatment alternative. With the availability of unlimited quantities of rhGH, researchers started to evaluate different treatment strategies with respect to dosing and timing and to evaluate the use of rhGH in children with short stature, but without classical growth hormone deficiency (GHD).
rhGH was approved by the FDA in GHD in 1985. In the following years it was approved for the treatment of various forms of short stature or growth failure, including: chronic renal failure (1995), Turner Syndrome (1993), Prader–Willi Syndrome (2000), small for gestational age without catch-up growth (2001), idiopathic short stature (2003), short stature homeobox containing gene (Shox) deficiency (2006) and Noonan Syndrome (2007).
The primary goal of rhGH treatment in GHD patients is to normalize height during childhood and adolescence and attain an adult height within the normal range and within the target height range (genetic potential).
Physiologic actions of growth hormone
The most important effect of GH therapy is to promote growth (height velocity), but GH has also important metabolic effects. Although generalized growth is stimulated, it is not evenly distributed among the protein, lipid, and carbohydrate compartments. In GH-deficient children, hGH therapy results in decreased body fat and increased fat free mass, including muscle and bone. Thus, proper GH secretion probably has major developmental influences on later health risks, including cardiovascular diseases and osteoporosis. The ability of insulin to promote fatty acid synthesis is antagonized by GH. Growth hormone induces a rapid loss of fat due to stimulation of lipolysis and reciprocal antagonism of the lipogenic actions of insulin [2].
GH drives a number of local bone effects, including: skeletal IGF-I synthesis; proliferation of prechondrocytes, hypertrophy of osteoblasts, bone remodeling and net mineralization [3].
Growth hormone stimulates cartilage growth. This is most evident as a widening of the epiphyseal plate, and is associated with an increase in amino acid incorporation into cartilage and bone [4]. Growth hormone also stimulates the uptake of sulfate by cartilage in vivo, but not in vitro. However, in vitro sulfate uptake is stimulated by serum from normal or hypophysectomized animals treated with growth hormone. This “sulfation factor” proved to be the insulin-like growth factor I (IGF-I) [5,6].
Genetic variability and rhGH treatment response
Investigators have used genome-wide association studies in a large number of subjects to identify genes related to adult height. As twin studies have shown in the past approximately 80% of adult height variation is genetically determined. In the initial studies height variation seemed to be associated with fewer than 50 loci within the human genome [7], a recent meta-analysis suggests that the number of genes controlling human height is much higher (hundreds) and the effect of every gene explains on average less than 1 mm of the variance in adult height [8].
Studies on the pharmacogenetics of rhGH have demonstrated that an isoform of the GH receptor gene that lacks exon 3 was associated with an increased growth response to rhGH than the full-length isoform [9]. A meta-analysis on this topic noted only a small difference of 0.5 cm in height velocity in the first year of rhGH therapy based on the isoform of the GH receptor [10]. Another study reported that the different isoforms of the GH receptor did not influence adult height in patients with severe GHD [11]. At the present time, data appear to demonstrate that the presence of the isoform of the GH receptor gene that lacks exon 3 may have a small benefit (increased height velocity) at the initiation of rhGH therapy, but not a significant impact in adult height. Another study evaluating the polymorphisms in the IGF binding protein 3 (IGFBP-3) promoter region showed that the first-year growth response of severe GHD children to rhGH is influenced by the −202 A allele of the IGFBP-3 promoter region [12]. In this study the first-year growth velocity of patients with the AA genotype was 13.0 cm compared to 10.8 cm in those with the CC genotype.
More extensive genetic studies with large sample sizes and adult height data are necessary to predict more effectively and hopefully improve the response to rhGH therapy.
Dosing and monitoring
There is a wide response to rhGH therapy, likely due to compliance issues, severity of GH deficiency and patient's sensitivity to rhGH. rhGH should be administered subcutaneously on a daily basis and the dose approved by the FDA is 25–100 μg/kg/day. Treatment should be started at the youngest possible age to achieve the greatest growth response.
Administration of growth hormone in the evening is sometimes suggested based on the rationale that this produces more physiologic patterns of growth hormone. However, there is no firm evidence that this approach is more effective than administration at another time of day.
The routine follow-up of pediatric patients receiving rhGH should be performed by a pediatric endocrinologist in partnership with the pediatrician or primary care physician. Children should be evaluated every 3–6 months.
Although some pediatric endocrinologists will use a fixed dose of rhGH, most will use an auxology-based dosing approach. This will involve starting at the lower end of the dose range and then titrating upwards based on the patient's response to therapy with measurement of IGF-1 concentrations to ensure that the patient is not overtreated or undertreated.
IGF-1 has pro-angiogenic and anti-apoptotic effects. Epidemiological studies indicate that elevated serum levels of IGF-1 may be associated with tumors in adults. Yet, no data demonstrate that supraphysiological IGF-1 levels during rhGH therapy cause tumor formation or progression.
Dose titration was initially based on weight and height velocity, but titration based on IGF-1 has also been analyzed, using this strategy, the rhGH dose is adjusted to a target IGF-1 level irrespective of height velocity and usual range of rhGH dose. One trial investigated the growth effects of adjusting rhGH dose based on serum IGF-1 concentrations by dividing the patients in three groups: in the first group, IGF-1 was to be kept in the upper limit of normality (+2.0 SD); in the second group, IGF-1 was kept close to the mean (0 SD); and the third group used a fixed rhGH dose [13]. The investigators found no significant differences in mean rhGH dose or height velocity between the fixed dose and IGF-1 targeted to 0 SD groups. The group targeted to an IGF-1 of +2 SD had a significantly greater height velocity, but required a much greater rhGH dose. The high cost of rhGH and the importance to minimize the risk of side effects of rhGH therapy favor a conservative approach. IGF-1 based rhGH dosing, targeted to age and gender adjusted means is a reasonable approach in terms of efficacy, cost-effectiveness and safety [14].
When rhGH therapy is administered at an early age, patients can achieve adult height within the midparental target height range [15].
If a prepubertal patient initially responds well rhGH treatment, but then fails to achieve the expected height velocity of the pubertal growth spurt, they may benefit from a temporary increase in rhGH dose (e.g., to 70–100 μg/kg/day), although that is uncommonly required [16]. The modest gains in height achieved by giving higher doses of rhGH during puberty must be balanced against the substantial costs of the additional growth hormone. In general, effective treatment with rhGH prior to puberty is more effective and cost-effective than efforts to boost growth during puberty.
Adverse effects
Treatment of children with rhGH has generally been safe [17,18].
Among children treated with recombinant growth hormone, the most common treatment-associated complaint is headache, which is usually benign. In addition, there appears to be a slightly higher risk of developing idiopathic intracranial hypertension (formerly known as pseudotumor cerebri), increased intraocular pressure, slipped capital femoral epiphysis, and worsening of existing scoliosis [19,20]. Whether these are true side effects of growth hormone itself or whether some are related to the rapid growth induced by growth hormone remains unknown.
Other rare adverse effects are pancreatitis, transient gynecomastia, and an increase in the growth and pigmentation of nevi, without malignant degeneration [21]. Carpal tunnel syndrome, edema, and arthralgia are more common in adults during growth hormone treatment, but are unusual in children. Most usually occur soon after therapy is initiated, and some of these effects are likely caused by sodium and water retention [22]. Development of insulin resistance and disorders of glucose tolerance may occur in children receiving growth hormone therapy, but the clinical significance appears to be low [23].
Analyses of databases tracking patients who have been treated with growth hormone in the modern era do not suggest an increased risk of malignancy following growth hormone treatment during childhood for growth hormone deficiency, although the length of follow up is still relatively brief [24–26]. In particular, the risk of leukemia has been extensively studied, both in the United States and Japan, and no significant increase in new cases or in the relapse of previous ones has been found despite several hundred thousand patient-years of exposure [27–29]. Similarly, treatment of childhood cancer survivors with growth hormone does not appear to increase the risk for secondary malignancy [30,31], except for the development of benign meningiomas after radiation treatment of certain primary brain tumors [32].
Growth hormone therapy at the transition from adolescent to emerging adulthood
Previously within this chapter we outlined the eight FDA-approved indications for therapy with rhGH for children and adolescents. There is only one indication, continuing GH deficiency, which is indicated in the emerging adult. In this section we shall identify whom to test, note various options for retesting, and consider various dosing strategies for those who continue to be GH deficient.
The transition from pediatric to adult-focused health care is a process that should occur for all adolescents/emerging adults irrespective of their health-care needs. That is, all adolescents require a transition. The number without chronic disease dwarfs those who do. In the context of GH deficient adolescents there will be many more who will not remain GHD as emerging adults than those that do. It is the identification of emerging adults in this smaller group that is key to this discussion.
Continuity of care is a main goal for all adolescents. It often means preparing for and taking on more of the responsibility for ongoing health care. The pediatric-based health care practitioner's main responsibilities are to be sure that medical needs are identified and the ongoing care noted. Communication with the new (adult-based) health care practitioner is often critical, especially for those with chronic health care needs. The age of transition is not fixed (in the US) but planning for the transfer, that is the transition process, should begin a number of years prior to that as the early adolescent becomes seemingly competent to begin the process and continue until transfer, and likely a bit beyond as some developments may not have been anticipated.
This process ([L. transition (-ovis), a passing over, from transitus, pp of transire, to pass over]) should begin long before the singular event of transfer ([L. transferre; trans, across and ferre, to bear]) and may be especially problematic for those with special health care needs.
Perhaps the easiest place to start would be those who do not require retesting to continue on to receive rhGH as emerging adults. That group would be those with known mutations, embryopathic lesions causing multiple pituitary hormone deficiencies, or irreversible structural lesions [33] Perhaps the maximum here would be to stop treatment with the adolescent dose of rhGH and after more than 2 weeks measure the circulating level of IGF-I. If it is more than 2 SD below the mean for age and sex, then one remains GHD as an emerging adult. In the US this step may be required for insurance purposes.
For all others treatment with rhGH should be discontinued for more than 4 weeks and IGF-I levels measured. For those above – 2 SD, one should perform two stimulation tests to determine ongoing GHD. There is no “gold-standard” test and those recommended [34] include: insulin tolerance test, glucagon, arginine and GHRH and arginine. The latter is not recommended for those with idiopathic GHD and has not been available for implementation in the US for a number of years. The flow diagram for patient evaluation and the specific cut-points for GH levels are shown in detail [34]. It should be noted that with arginine alone the cut point is very low (0.4 μg/L) that may be problematic in some commercial assays for hGH.
Once the diagnosis of (emerging) adult GHD is confirmed one has the issue of the dose of rhGH given that the late adolescent dose is often 5-fold that for the adult. There are not any consensually validated guidelines for how to get from one dose to the other. It is clear that GH deficient adults become quickly symptomatic on doses of rhGH that are above their replacement needs and well below the adolescent dose. A prudent method takes into account the time since the last therapeutic dose of rhGH. If testing has been done in the few months since stopping rhGH therapy, then beginning a perhaps 1⁄2 the adolescent dose and decreasing the dose every few months as one move toward the adult dose is safe and effective. As noted for adults one wishes to keep the circulating IGF-I levels above 0 SD, but below +2 SD. If the patient has been without GH replacement for more than 6 months (many of these patients have been off therapy for years and just tumbled to the reason for their symptoms), then starting at the adult dose, perhaps 0.3–0.8 μg per day (total dose) is appropriate and titrating the dose upward to the same IGF-I levels noted above. By doing the latter one is less likely to have the early side effects of water retention and joint pain.
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Recombinant Human Growth Hormone
Full-body catabolism is one of the hallmarks of the hypermetabolic response to severe burn injury. The underlying mechanisms responsible for severe muscle atrophy are not fully understood. One established mechanism is a decrease in the endogenous hormone IGF-1, which is responsible for anabolic properties in adults and growth in children. Levels of IGF-1 are significantly reduced after severe burn injury.11,80 Growth hormone, which used to be extracted from pituitary glands of corpses to treat children with growth retardation, has been found to be beneficial in mitigating the reduction of IGF-1 in catabolic patients. The genetically engineered recombinant growth hormone (rhGH) in use today increases the release of IGF-1. Other anabolic effects consist of increasing nitrogen retention, increasing cellular uptake of amino acids, and increasing protein synthesis. Because there are growth hormone receptors on epidermal cells, rhGH has beneficial effects directly on skin.81 When administered intramuscularly to severely burned pediatric burn patients at a dose of 0.2 mg/kg/day, rhGH significantly increased endogenous levels of IGF-1 and lean body mass, and reduced donor site healing times, total cost of care, and scarring.81–87 Larger, more adequately powered studies need to be done before this can be become standard of care.
rhGH significantly improved the immune response postinjury. It significantly decreased serum tumor necrosis factor-α, interleukin-1, serum amyloid-A, and C-reactive protein. It enhanced T-helper-1 and reduced T-helper-2 cytokine production, a consequence of burn injury that is potentially fatal in severely burned patients.88–91 It improved the hepatic acute-phase response and increased albumin production.88,89,92–94 There were significant improvements in weight gain, bone mineral content, height velocities, and cardiac function.95,96 These effects were seen up to 3 years postinjury.97,98
The most notable side effect from the use of rhGH was hyperglycemia.94,99 The most updated Cochrane Database analysis found no increase in mortality or sepsis. Admittedly the collective studies are not powered enough to find statistically significant results in these categories; it would be prudent for a larger more powered study to be done to comprehensively study this potential modulator.81,94 rhGH may safely be used in pediatric burn patients to attenuate the hypermetabolic response with close monitoring to prevent adverse outcomes.
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Anabolic steroids and growth factor therapy
Anabolic steroids and other hormones have been studied as adjunctive therapies to modulate the typical catabolic state following severe injury and major surgery. The most studied agents include recombinant human growth hormone, oxandrolone, and megestrol acetate.
Growth hormone is a peptide released from the pituitary gland that stimulates the production of insulin-like growth factor 1 and thus suppresses proteolysis and increases protein synthesis, muscle growth, and lipolysis. At present, indications approved by the Food and Drug Administration for recombinant growth hormone include human immunodeficiency virus (HIV) wasting syndrome, total parenteral nutrition dependent short bowel syndrome, and pediatric chronic kidney disease. In addition, small studies have demonstrated improvement in lean body mass in malnourished patients with chronic obstructive pulmonary disease. The evidence in surgical patients is limited. A small study of 14 patients on long-term nutritional support for severe GI dysfunction published in 1993 demonstrated improvement in lean body mass and protein synthesis.71 However, 2 subsequent prospective trials showed that administration of recombinant growth hormone in critically ill patients was associated with increased morbidity and mortality because of multiorgan failure, septic shock, and infection.72
Megestrol acetate, a synthetic progesterone, has been demonstrated to stimulate appetite and cause weight gain in patients with cancer.73 The exact mechanism of action and optimal dose are unknown, but the weight gain seems to be mainly secondary to an increase in body fat and not lean body mass.74,75 Megestrol acetate increases the risk of thromboembolic complications, especially at higher doses, and can induce transient adrenal insufficiency.74 Data evaluating its effectiveness in surgical patients are limited.
Oxandrolone is an enterally administered synthetic derivative of testosterone that has 10 times more anabolic effects and only 10% of the adverse androgenic effects of testosterone. This anabolic steroid stimulates protein synthesis, counters the catabolic effects of cortisol through competitive inhibition of the glucocorticoid receptor, increases intracellular amino acid influx and use, and improves efficiency of skeletal muscle protein synthesis.76 Oxandrolone has been studied in several catabolic disease states, including burn injury, trauma, HIV-related wasting, and neuromuscular disorders. In several small but prospective randomized studies in patients with severe burn injury, oxandrolone decreased weight loss and nitrogen loss and improved wound healing time without a significant difference in the rate of complications.76 However, in trauma patients and in ventilator-dependent surgical patients, oxandrolone administration does not seem to be beneficial.77,78 Oxandrolone was well tolerated in most studies with the most common side effect of mild increases in aspartate transaminase, alkaline transaminase, and alkaline phosphatase levels.
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Treatment
Replacement with recombinant growth hormone therapy is the standard of treatment for infants diagnosed with deficiency. Guidelines for growth hormone treatment established by the Pediatric Endocrine Society state that an initial GH dose should be 0.16 to 0.24 mg/kg/week or 22 to 35 mcg/kg/day.27 Some manufacturers have recommended higher doses up to 0.3 mg/kg/week in prepubertal children, but the provider should recognize that a decision to treat an infant with recombinant growth hormone is in part dictated by preventing ongoing hypoglycemia and not just to promote normal growth; the higher doses are generally not required to alleviate hypoglycemia.
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