5
Treatment of growth hormone deficiency in children, adolescents and at the transitional age

https://doi.org/10.1016/j.beem.2016.11.005Get rights and content

Recombinant human growth hormone (rhGH) has been available since 1985. Before 1985 growth hormone (GH) 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. 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). Genome-wide association studies have been used increasingly to study the genetic influence on height. There is a wide response to rhGH therapy, likely due to compliance issues, severity of GH deficiency and patient's sensitivity to rhGH. While 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 over treated or undertreated. Although treatment of children with GHD with rhGH has generally been safe, careful follow-up by a pediatric endocrinologist in partnership with the pediatrician or primary care physician is recommended.

The aim of this paper is to review the strategies and recommendations for treatment of GHD in children and patients in the transition to adult care.

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).

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].

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.

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.

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], [25], [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], [28], [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].

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 ½ 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.

Section snippets

Summary

The use of rhGH to treat children with short stature resulting from GHD has now accrued more than 30 years of clinical experience with a satisfactory safety and efficacy record. The most important effect of GH therapy is to promote height velocity, but GH has also important metabolic effects. In GH-deficient children, GH 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

References (34)

  • A.R. Wood et al.

    Defining the role of common variation in the genomic and biological architecture of adult human height

    Nat Genet

    (2014)
  • C. Dos Santos et al.

    A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone

    Nat Genet

    (2004)
  • M.J. Wassenaar et al.

    Impact of the exon 3-deleted growth hormone (GH) receptor polymorphism on baseline height and the growth response to recombinant human GH therapy in GH-deficient (GHD) and non-GHD children with short stature: a systematic review and meta-analysis

    J Clin Endocrinol Metab

    (2009)
  • B. Räz et al.

    Influence of growth hormone (GH) receptor deletion of exon 3 and full-length isoforms on GH response and final height in patients with severe GH deficiency

    J Clin Endocrinol Metab

    (2008)
  • E.F. Costalonga et al.

    The −202 A allele of insulin-like growth factor binding protein-3 (IGFBP3) promoter polymorphism is associated with higher IGFBP-3 serum levels and better growth response to growth hormone treatment in patients with severe growth hormone deficiency

    J Clin Endocrinol Metab

    (2009)
  • P. Cohen et al.

    Variable degree of growth hormone (GH)- and insulin-like growth factor (IGF)- sensitivity in children with idiopathic short stature (ISS) compared to GH-deficient (GHD) patients: evidence from an IGF-based dosing study of short children

    J Clin Endocrinol Metab

    (2010)
  • P. Cohen et al.

    Dose-sparing and safety-enhancing effects of an IGF-I-based dosing regimen in short children treated with growth hormone in a 2-year randomized controlled trial: therapeutic and pharmacoeconomic considerations

    Clin Endocrinol (Oxf)

    (2014)
  • Cited by (0)

    View full text