The benefits of growth hormone therapy in patients with Turner syndrome, Noonan syndrome and children born small for gestational age

Growth Hormone & IGF Research 21 (2011) 305–313

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Review

The benefits of growth hormone therapy in patients with Turner syndrome, Noonan syndrome and children born small for gestational age Anne-Marie Kappelgaard a,⁎, Torben Laursen b a b

Novo Nordisk A/S, Copenhagen, Denmark Department of Pharmacology, University of Aarhus, Denmark

a r t i c l e

i n f o

Article history: Received 22 June 2011 Received in revised form 26 September 2011 Accepted 27 September 2011 Available online 20 October 2011 Keywords: Growth hormone Subcutaneous injection Turner syndrome Noonan syndrome Short children born small for gestational age Adherence

a b s t r a c t This review will summarize the effects of growth hormone (GH) on height, body composition, bone and psychosocial parameters in children with Turner syndrome or Noonan syndrome and those born small for gestational age. The safety of GH treatment in children with these diagnoses is also reported. Despite the reported efficacy and safety of GH in these indications, however, not all children achieve their target height potential, due in some part to poor adherence to GH therapy regimens; indeed up to 50% of children are less than fully compliant with treatment. With this in mind the present and future administration of GH therapy is discussed with respect to advances being made in the presentation of GH for injection and advances in GH injection devices. It is hoped that such progress, aimed at making the administration of GH easier and less painful for the patient will improve treatment adherence and outcome benefits. © 2011 Elsevier Ltd. All rights reserved.

1. Introduction The therapeutic benefit of growth hormone (GH) therapy in improving height in short children with GH deficiency (GHD) is well documented with the primary aim of treatment being to normalize height to within, or even above, genetic potential [1]. With the approval of GH therapy for several new indications such as Noonan syndrome (NS), small for gestational age (SGA) and idiopathic short stature (ISS), adding to the more established indications including Turner syndrome (TS), chronic renal failure, and Prader– Willi syndrome, there are now many approved uses in pediatric patients. GH treatment of the child with GHD is universally accepted, with well-established clinical criteria for starting treatment. There are, however, ethical, economic and psychosocial issues associated with the use of GH therapy in children, requiring that sound clinical practice should include an individualized approach to any patient who may be a potential candidate for GH treatment. Thus, in patients with TS and those with short stature born SGA, it may be as important to address psychological adjustment as to normalize height because, phenotypically, the children may appear different from other children, as well as having other health-related issues. In Prader–Willi syndrome the effect of GH in normalizing body composition may be as important as its effect on height. In almost all of these conditions, treatment involves daily subcutaneous (sc) injections of GH, often

⁎ Corresponding author at: Global Marketing GHT, Novo Nordisk A/S, Hummeltoftvej 49, DK-2830 Virum, Denmark. Tel.: + 45 44 42 1650; fax: + 45 44 42 16 30. E-mail address: [email protected] (A.-M. Kappelgaard). 1096-6374/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ghir.2011.09.004

for many years. Due to the length of treatment, patient adherence to the prescribed treatment regimen is one of the most important factors that determines the success, or otherwise, of treatment [2]. This review examines the benefits of GH therapy in children, with particular emphasis on short children born SGA, and those diagnosed with TS and NS. The potential for improving treatment adherence during long-term GH therapy with the use of a liquid GH preparation and improved injection devices is also examined. 2. Definition, incidence, prevalence and characteristic features of small for gestational age, Turner syndrome and Noonan syndrome 2.1. Small for gestational age and intrauterine growth retardation It is estimated that approximately 3–5% of infants are born SGA. The internationally accepted definition of SGA is a birth weight and/ or length less than −2 standard deviation scores (SDS) [3]. SGA is not always the same as intrauterine growth retardation (IUGR) as the latter implies insufficient fetal growth, whereas SGA refers to a fixed condition identified at birth that may not be related to IUGR. Hence, a child can be born SGA due to IUGR or due to low midparental height (i.e. infant fetus growing at a normal rate [no IUGR]). Approximately 10% of infants born SGA maintain their height at −2 SDS and remain short throughout childhood and adolescence, achieving an adult height 1 SDS or more lower than the mean [4,5]. Indeed, those born SGA who remain short into adult life form a relatively high proportion, estimated at around 2.3%, of all adults with short stature [6,7]. Premature infants born SGA have a different

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pattern of postnatal growth, experiencing catch-up growth at a later stage than full-term infants born SGA [8]. Children born SGA comprise a heterogenous group with a broad spectrum of clinical characteristics apart from short stature, including a low lean body mass, often with increased central adiposity. Premature infants born SGA with IUGR may be at particular risk for high insulin levels in infancy and are significantly smaller than full-term infants born SGA without IUGR [9].

and within the genetic target range). GH therapy was initially used in children with short stature due to GHD. In these children, GH therapy can help to normalize height during childhood and many achieve a normal adult height [22]. The best results are found in children with severe GHD as well as a low predicted adult height in whom treatment with appropriate GH doses is started as early as possible after diagnosis [23]. 3.2. Small for gestational age

2.2. Turner syndrome TS is a congenital disorder with a combination of characteristic phenotypic features caused by the loss of the entire X chromosome, or loss of a critical part of it [45,X]. The genetic background of the TS phenotype is highly variable, but involves complete or partial absence of the sex chromosomes (the X and/or Y chromosomes). In addition mosaicism with two or more cell lines may be present. The classical karyotype 45,X accounts for about 50% of cases, with the remaining being mosaic karyotypes (i.e. cells with 45,X and cells with 46,XX) [10]. It is the most common sex chromosome abnormality in females, affecting approximately 3% of all female fetuses, although due to high fetal wastage only 1% of these embryos survive to term [11]. Estimates suggest that the number of females born with TS ranges from 25 to 210 per 100,000 of all live births, or 1:2000 to 250 live born girls. The estimated prevalence of TS is 40– 50 per 100,000 women [12]. The wide range of somatic features in TS results from the fact that a number of different X-located genes are responsible for the complete phenotype [13]. Typical stigmata include short stature, primary amenorrhoea, estrogen insufficiency and cardiovascular malformations. Untreated, the average adult height deficit in women with TS is 20 cm, with the average height being 147 cm. 2.3. Noonan syndrome This is a clinically heterogeneous autosomal dominant condition [14] that occurs with equal prevalence in both males and females in between 1:1000 and 1:2500 live births [15]. In approximately 50% of cases, NS is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. Recently, mutations in the KRAS gene as well as mutations in RAF 1, SOS 1, NRAS, and BRAF, have also been identified in a small proportion of patients with NS [16–20]. Phenotypic overlaps between NS and a number of other syndromes including LEOPARD, cardio-facio-cutaneous syndrome and Costello syndrome have been identified. Although they may be difficult to distinguish early on in life, with time they can generally be distinguished clinically. Patients with LEOPARD, a rare syndrome with many features similar to NS, commonly exhibit mutations in the PTPN11 gene, although at a different locus to those involved in NS. Patients with Costello syndrome exhibit severe growth retardation postnatally as well as significant motor and mental delay, although physically they may be indistinguishable from patients with NS. Although there is a wide phenotypic variation in NS, the most prominent clinical features include proportionate postnatal short stature, typical facial dysmorphic features, chest deformities and congenital heart disease [15]. Data indicate a mean adult height of 162.5 for men and 152.7 cm for women [21]. 3. Rationale for initiating GH therapy 3.1. Improves height In short children, the aim of GH therapy is to achieve normal height in early childhood and to maintain growth in order to normalize adult height (i.e. height within the normal range for age and sex,

Subtle defects in the GH-insulin-like-growth-factor-I (IGF-I) axis may contribute to the poor postnatal catch-up growth in children born SGA who do not get into the normal height range. Genetic abnormalities and polymorphisms in the GH–IGF-I axis have been found in association with small size at birth. Environmental factors may also re-program growth during fetal development, leading to altered hormone sensitivity in short children born SGA [24,25]. Several observations point toward impaired sensitivity to hormones involved in the GH–IGF–IGF binding-protein (IGFBP) axis, but large variations in hormone sensitivity patterns make it difficult to classify patients born SGA according to the relative GH and IGF-I concentrations. This impaired hormone sensitivity along the GH–IGF–IGFBP axis may complicate the therapeutic possibilities for treating short stature in this population. Several studies demonstrated that GH treatment in short children born SGA results in normalization of height during childhood and adulthood, while untreated children show no improvement in growth [3,26–31]. During GH treatment in children born SGA, there is a rapid increase in total IGF-I levels and a slower increase in IGFBP-3 levels [32]. Debate exists concerning the role of total IGF-I and/or IGFBP-3 levels in the growth response. Some studies suggest that the growth response shows a positive association with the short-term increase in total IGF-I [32] and an inverse relation to baseline IGF-I levels [32,33]. Other authors [34] report a positive correlation or no relationship [35] between the growth response and the change in both total IGF-I and IGFBP-3 in children born SGA. Official indications for the use of GH in short children born SGA by the Food and Drug Administration (FDA) (2001) and by the European Medicine Agency (EMA) (2003) differ slightly in their guidance. The FDA indicates that treatment should be started in short children with SGA at the age of two years. The EMA indication suggests that treatment is started at the age of 4 years in short children with SGA with a height below 2.5 SDS, growth velocity of 0 SD for age, and height 1 SD below midparental height SDS. Based on these recommendations, a consensus statement from the International Society of Pediatric Endocrinology and Growth Hormone Research Society suggests that short children born SGA who are under 2 years of age with a current height SDS b −2.5 should be referred for evaluation [3]. Children born SGA who are 2–4 years of age showing no evidence of catch-up, with a height SDS b − 2.5 should be eligible for GH treatment, and children born SGA who are more than 4 years old showing no evidence of catch-up growth should be treated at a height SDS of b−2 or maybe −2.5 [3]. Predictors of a positive response to GH therapy within the first 2–3 years of treatment include age and height SDS at start of treatment (a smaller height SDS is predictive of a better response [36]), midparental height, GH dose and pretreatment IGF-I levels [37]. In an observational study, height gain was shown to be significantly greater when children were treated from the age of 1–3 years and preferably for at least 2 years before puberty [38]. When GH treatment was started at 7–8 years of age, a gain in adult height of +2 SDS was reported in a randomized, double-blind, dose response trial, in contrast to a height gain of around + 0.6 SDS if GH is was started at approximately 10–12 years of age [28]. Average height increases following 3 years of GH treatment range from 1.2 to 2.0 SDS for doses of 0.035–0.070 mg/kg/day, with most of

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the height gain maintained until adult height. Higher GH doses are needed in children born SGA to induce a growth response comparable to that of patients with GHD. In randomized, controlled, studies the response to GH was shown to be dose dependent for up to 6 years [39,40], with a better growth response, equivalent to a 2.5 cm higher adult height, reported using a higher (0.067 mg/kg/day) compared with a lower (0.033 mg/kg/day) GH dose [36]. The maintenance phase of growth appears to be less dose dependent than the growth phase [36]. In a prospective, randomized, double-blind, dose–response study, after 6 years of treatment (0.033 or 0.067 mg/kg/day), almost every child's height was within the normal height range with children in the higher dose group having a greater height SDS increment than those in the lower dose group (2.5 vs 2.0 SDS, respectively) [30,41]. Follow-up of this cohort after a mean (SD) treatment duration of 7.8 (1.7) years showed that 85% of patients had achieved an adult height above − 2 SDS and 98% reached an adult height within the target height range (Fig. 1) [28]. Mean adult height for patients represented an increase of approximately 12 cm compared with untreated control subjects and was not significantly different between dose groups [28,42]. In an observational Swedish study using a GH dose of 0.033 mg/kg/day, the adult height was equivalent to a 9 cm gain over the predicted value [38]. In a meta-analysis of data from four randomized controlled trials [28,38,43] (n = 391) the adult height of patients in the GH treated groups was significantly greater than that in the control groups, with a mean between groups difference of 0.9 SDS (5.7 cm) (pb 0.0001) [44]. The Swedish study also reported that the best growth response was obtained in the youngest, shortest and lightest children. Starting treatment at least 2 years before puberty seems to be appropriate. When treatment is started late, a higher initial GH dose might be proposed. A randomized, parallel-group study in children born SGA (n = 151, age 3–8 years) comparing outcomes after continuous versus discontinuous therapy reported similar height gains after 2 years using 1) 0.1 mg GH/kg/day for 1 year followed by a year without GH; 2) 0.033 mg GH/kg/day for 2 years; or 3) no treatment for 1 year followed by 0.067 mg GH/kg/day for 1 year [31]. Using individually tailored doses of GH may provide a more optimal growth outcome [45]. In children responding inadequately to GH (height velocity SDS b0.5 in the first year of treatment), treatment should be re-evaluated, including consideration of compliance, GH dose, diagnosis and the possibility of discontinuation of treatment. GH treatment can be discontinued in adolescence when growth rate declines to below 2 cm/year. For children with short stature following IUGR, short-term GH therapy can induce sustained catch-up growth in young children, similar to that observed in patients born SGA without concomitant IUGR [46].

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response during the first year of therapy [49]. In a controlled Canadian trial, girls with TS (aged 7–13 years) who were randomized to receive GH (0.3 mg/kg/week) or placebo, both accompanied by estrogen replacement therapy from the age of 13 years achieved an adult stature 7.2 cm taller than a group of historical controls after a mean treatment period of 5.7 years, and 93% were within normal height range within 2 years. Tall height and young age at study start, tall parental heights, long duration of treatment and use of higher GH doses predicted a taller adult height [56]. Although the optimal age for starting GH therapy has not been established, a study in 88 girls between the ages of 9 months and 4 years, who were randomized to GH or no GH therapy, suggested that GH therapy is effective at 9 months of age [57]. To overcome the retarded growth in patients with TS, most studies have shown that high doses of GH are needed, indicating the presence of GH or IGF-I resistance [51,53]. The dose can be monitored by the patient's growth response and serum IGF-I levels (e.g. every 3–6 months). In a Dutch study, the mean (SD) gains in final adult height in response to GH doses of 0.045 mg/kg/d, 0.067 mg/kg/day and 0.089 mg/kg/day were 11.9 (3.6), 15.7 (3.5) and 16.9 (5.2) cm, respectively [53]. The higher GH doses, however, raised serum IGF-I levels to above the normal range in some subjects [58]. In girls older than 9 years of age and in girls with extreme growth retardation, higher GH doses (1.3 mg/m 2/day) and/or low-dose GH (0.6 mg/m2/day) plus a non-aromatizable steroid (e.g. oxandrolone) are most effective, with the latest data suggesting that a low-dose GH regimen might be better tolerated and more effective than higher doses [59]. Later on addition of estrogen is often required to induce puberty. Evidence suggests that some treatment regimens using estradiol from the age of 12 years result in normal puberty without interfering with the effects of GH on final adult height [53]. GH treatment is usually continued until an appropriate height is achieved or growth is ceasing (bone age N14 years and growth velocity b2 cm/year) [49,57].

3.3. Turner syndrome The reduction in adult height in TS is explained, at least in part, by haploinsufficiency of the SHOX gene, located in the PAR1 region of the X and Y chromosomes [47]. The variation in the degree of growth retardation between individuals with TS appears to be unrelated to mosaic status or single gene loss [48]. GH treatment of short stature associated with TS is well established on the basis of over 20 years of data from clinical trials [49–52]. Despite the fact that GH deficiency is not apparent in TS, the GH–IGF-I–IGFBP-3 axis is disturbed and increased levels of IGFBP-3 proteolytic activity have been described in adults with TS in association with low circulating levels of IGF-I. Significant gain in height over predicted adult height following GH therapy and sex steroid replacement therapy has been reported by a number of investigators [52–55]. Current recommendations in Europe support the use of a flexible GH dose (0.045–0.067 mg/kg/day) in girls with TS, dependent on age and severity of growth retardation as well as on the treatment

Fig. 1. Bottom panel: height SDS (SD) during GH treatment and at AH in relation to TH. Top panel: gain in height SDS (SD) from the start until 2 years of GH treatment, until 5 years of GH treatment and until AH. Group A: 0.033 mg/kg/day GH; Group B: 0.067 mg/kg/day GH AH, adult height; GH, growth hormone; SDS, standard deviation score; TH, total height. Reproduced from Y. van Pareren et al. J. Clin. Endocrinol. Metab. Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose–response GH trial. 88 (8) 3584–3590. Copyright 2003, The Endocrine Society [28].

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3.4. Noonan syndrome Despite identification of genetic mutations contributing to the broad heterogeneity of NS, which leads to significant height discrepancies, the cause of the short stature has not been identified. Although SHP2 enhances Ras-MAPK signaling, it downregulates Jak2/STAT5b signaling of the GH receptor, according to in vitro data. Decreased IGF-I levels have been measured in those children with NS who carried PTPN11 mutations, suggesting a mode of mild GH insensitivity. The shortterm responsiveness to GH therapy in NS with respect to PTPN11 mutations has been shown to be mildly reduced in the presence of PTPN11 mutations; relevant long-term data, however, are missing. In a small subgroup of patients with NS, tumor risk is increased and is associated with specific mutations of Ras-MAPK pathway genes, including PTPN11. Hence use of long-term GH therapy to promote growth in children with NS has to be considered in relation to the genotype, the effective promotion of growth and the potentially increased tumor risk. Progress in the understanding of cell regulation by Ras-MAPK signaling is hoped to provide more evidence on which therapy might be helpful in the care of children with NS [60,61]. Most of the evidence for the effects of GH on growth in NS has come from observational studies in small numbers of subjects and without randomization or control groups. Doses between standard replacement doses and higher doses such as those used in TS have been employed. The US Food and Drug Administration has approved treatment of NS with GH using doses up to 0.066 mg/kg/day. Shortterm growth acceleration comparable to that seen in TS has been reported [62]. Despite a reported waning of the response over time [63], sustained catch-up growth, at least until puberty, has been demonstrated over longer treatment periods [14,60–63]. In an uncontrolled study, 18 children who reached final height after a mean treatment period of 7.5 years of GH therapy reported an increase in mean (SD) height SDS during treatment from − 2.9 (0.4) at treatment start to − 1.2 (1.0) at final height. This was equivalent to an increase of 10.3 cm compared with predicted adult height. The initial GH dose in this study was 0.033 or 0.066 mg/kg/day [14]. Adult height after prolonged GH treatment has only been reported in few studies [67]. Other NS studies have shown that the overall height gain of patients is small (5–10 cm), and that treatment usually begins at the age of about 10 years, at a height of approximately −3.0 SDS [64,65,66,68]. This small response to treatment reflects the external treatment conditions (i.e. late age at GH start, low GH dose), but may also be associated with the fact that impaired sensitivity to GH is common. One such study only found an increase in adult height of 0.8 SDS (3 cm) after a mean of 5.3 years GH treatment in 10 patients [65]. In another study, the mean gain in height SDS in 22 children with a mutation in PTPN11, which is suggested to influence height velocity and adult height, was 1.3 SDS and was not different to that in five children without a mutation in PTPN11 (1.3 SDS; p = 0.98) [66]. Indeed, even though the response to GH therapy appears to wane, more than 50% of patients in a cohort of 402 achieved an adult height greater than − 2 SDS according to Tanner standards [64]. Comparison of near adult heights of children treated with GH with either NS or TS found no significant difference in Δ height SDS (1.4 [0.7] vs 1.2 [0.9], respectively) [68]. By contrast, Δ height SDS for patients with NS and TS differed significantly from idiopathic GHD (1.7 [1.0] SDS; p b 0.0001). Duration of prepubertal GH and height SDS at puberty are important contributors to near adult height in this population [68] suggesting that greater growth optimization is possible with earlier initiation of therapy. 4. Other benefits of GH therapy It is now accepted that adults with severe GHD demonstrate impaired physical and psychological well-being and may benefit from

treatment with recombinant human GH. Indeed the benefits of GH therapy on body composition, lipid and glucose homeostasis, cardiac performance, bone mineral density, and quality of life have clearly been shown in adults with GHD. The clinical impact of GH on aspects of health apart from height should necessarily also be considered in pediatric patients. 4.1. Effects on body composition, lipid profile and cardiovascular status GH therapy has beneficial effects on body composition, blood pressure and lipid metabolism in short children born SGA. In a 6year study of 79 patients, body mass index SDS was normalized in response to GH therapy [30]. This was found to be due to increased muscle mass rather than changes in percentage body fat. Increased muscle mass in association with GH therapy has likewise been demonstrated in short children born SGA in other studies [6,40,69,70]. As well as the trend toward improved body size, insulin resistance, hypo-HMW-adiponectinaemia, hypertriacylglycerolemia, and an amplification of the deficit in sc fat have also been reported [71]. The Ala12 variant of the PPAR-gamma gene is associated with higher weight gain during GH treatment but not with changes in determinants of metabolic and cardiovascular diseases in Caucasian subjects born SGA [72]. Increased lean body mass and reduced adiposity have also been reported during GH therapy in girls with TS [73,74]. As well as reduced lean body mass, short prepubertal children born SGA have lower intake of calories, fat and carbohydrates than their healthy peers. Initiation of GH therapy is associated with a marked increase in food intake, and a reduction in leptin levels suggests that this feedback loop is intact in children born SGA [70]. Beneficial effects of GH therapy on plasma lipoprotein profile have been reported in children with TS [51,75] as well as in short children born SGA [28,78]. In both children born SGA and girls with TS these changes comprise clinically relevant improvements in the atherogenic index (ratio of total cholesterol/high-density lipoprotein [HDL]-cholesterol) as well as plasma HDL-cholesterol levels. 4.2. Effects on bone Although the increase in longitudinal bone growth with GH therapy is well recognized, several studies have described improved bone mineral density after GH therapy in short children born SGA [34,76], and in TS and other indications [77]. A marked increase in cortical bone area has been demonstrated in short children born SGA following GH therapy [78] but not in girls with TS [73]. The clinical relevance of the enhancement of bone mineral density is unknown. However, GH treatment may be associated with improved bone strength and a potential reduction in the risk for osteoporosis and fractures, which have been reported as features of GHD in adults. The time of initiating GH therapy might be crucial, as patients with GHD who received early GH therapy do not present with an increased number of vertebral fractures [79]. Furthermore, peak bone mass is achieved later in conditions of delayed puberty or hypogonadism [80,81], and thus continuing GH therapy for a period after growth has ceased might be considered. 4.3. Psychosocial benefits In addition to the acknowledged improvements in physical parameters, GH therapy is reported, at least in some studies, to be associated with psychosocial benefits [82–87]. Short stature, per se, is often associated with negative stereotypes and psychological disadvantage [82], including underachievement at school, behavioral problems and reduced social competency. Although some reports suggest that these deficiencies may be attributed to a child's short height [83], other studies report no clinically relevant increase in such problems in children with short stature compared with their

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normal-height peers [84]. A report by van Pareren et al. [85] documented improvements in performance and total IQ, total problem scores and increased self-perception in short children born SGA treated with GH. In another study, Bannink et al. [86] reported an improved quality of life score in adolescents born SGA treated with GH. Health-related quality of life (HRQoL) evaluations in young women with TS who received long-term replacement therapy with GH and sex steroids showed that those who achieved normal height and who had age-appropriate pubertal development had high scores on the HRQoL scales, including ‘social functioning’ and role-emotional scales [87]. 5. Safety of GH therapy The safety of GH therapy in children has been an issue of much discussion. In general, treatment with GH is well tolerated in children [88]. Most reported side-effects are of a minor, or self-limiting nature (e.g. local injection site reactions, nausea, headache and fever) [89]. Other side-effects such as edema or carpal tunnel syndrome, which are related to GH-associated fluid retention, are generally transient, and fully resolve within the first few weeks of GH treatment or in response to GH dose reduction [90]. Data suggest that GH does not negatively influence body proportions, unduly accelerate skeletal maturation, or alter the onset or tempo of puberty or growth during puberty in short children born SGA. The effect of GH on glucose metabolism in children born SGA is of potential concern in view of their predisposition for developing metabolic disease in adult life [91–93]. The effects of GH on glucose metabolism have, however, been addressed in many studies and, although insulin levels increase significantly from baseline during GH therapy both in patients born SGA and in girls with TS, no glucose intolerance is evident and insulin levels return to normal levels on completion of the GH therapy [30,75,87,94]. In a recent study of 37 young adults born SGA and treated with GH during childhood for a mean period of 7.3 years, there was no increased risk of metabolic syndrome or type 2 diabetes mellitus evaluated after a mean period of discontinuation of GH of 6.5 years compared with untreated individuals born SGA [94]. Most effects on glucose metabolism seem to reverse after cessation of treatment. As in GHD, potential untoward effects of GH on insulin sensitivity might be opposed by improved body composition (e.g. reduced visceral fat mass). Despite concerns regarding the impact of GH therapy, via its mediator IGF-I, in the development of cancer, recent data [95] even suggest an inverse association between IGF-I and IGFBP-3 levels and all-cause mortality in women. No evidence of an increased risk of cancer has been shown in children previously treated for neoplasm [96], particularly when IGF-I levels are maintained within the normal range [97]. Hence, while the main role of GH replacement therapy in a pediatric population has generally been considered to be improvement of height, it is evident that beneficial effects on lipids, bone density and body composition should also be taken into consideration. 6. Present and future aspects of mode of GH administration Biosynthetic recombinant human GH is administered as daily sc injections. Most patients prefer injections in the thigh; however similar pharmacokinetic and pharmacodynamic effects are obtained following injections in the thigh and abdomen, although the absorption is slightly faster from the abdominal site [98]. Administration of GH in the evening results in elevated serum GH levels during the night and low levels during the day, mimicking the physiological pattern of GH secretion. Moreover, evening injections produce increased lipolytic and protein-sparing effects during the night and less stress on insulin sensitivity during the day, which is preferable from a metabolic point of view [99]. Daily sc injections do not, however, imitate true

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nocturnal pulsatile GH secretion, as peak concentrations following injections are obtained after 3–5 h, and circulating GH levels are constantly elevated during the night, and remain in the circulation for up to 16–20 h. Despite these differences, this regimen effectively promotes growth in children with GHD and increases serum IGF-I levels. Studies comparing daily sc injections in the evening with a constant sc infusion of GH for 4–26 weeks have demonstrated comparable metabolic effects, as evaluated, for example, by the GH–IGF axis, insulin sensitivity, bone markers and lipoproteins [100,101]. Thus, long-acting preparations of human GH, that also result in elevated GH levels for a sustained period, might be as effective as daily injections for growth promotion, and the patients will need fewer injections. Several approaches have been taken to develop long-acting forms of GH, including pegylated GH, GH microspheres, crystalline GH, and hyaluronate-conjugated GH [102]. These preparations result in a sustained concentration of GH that can be maintained for several days or even longer, allowing for weekly, or in some cases bi-monthly, injections. Evaluation of these GH formulations in adult and pediatric patients with GHD suggests that they are able to provide comparable changes in anthropometric parameters to those seen with daily GH injections [103–108]. There may, however, be a more marked serum IGF-I increase with continuous GH exposure [109,110]. Although the sideeffect profiles from short-term studies are encouraging, more longterm experience is being sought to establish the absolute safety profile [102]. Prolonged supraphysiological GH levels as seen in acromegaly are known to be associated with metabolic risk, such as insulin resistance or diabetes [111,112]. However, potential insulin antagonistic effects of GH administered in therapeutic doses are counteracted by beneficial changes in body composition secondary to the lipolytic and protein conserving effects of GH. Long-acting GH preparations used for physiological replacement therapy will not produce sustained elevated GH levels similar to those seen in acromegaly, and furthermore circulating GH levels will fluctuate to some extent. In short-term studies of 1–6 months constant delivery of therapeutic GH doses do not impair insulin sensitivity [113,114]. 6.1. Adherence to GH therapy affects treatment outcome To achieve optimal therapeutic results with GH, continuous, longterm adherence is essential. GH replacement therapy requires daily sc injections [115]. Injection frequency has been found to be associated with growth response [116–119]. Height velocity in pediatric patients treated with GH who missed N15 injections/month was only 69% of that achieved by patients who missed 4–15 injections/ month (Fig. 2) [118]. In another study, concordance with GH in 75 children assessed through data on general practitioner prescriptions showed that 23% missed N2 injections/week and that lower concordance was associated with significantly reduced height velocities (p b 0.05) [119]. Therefore, in patients who do not adhere to the prescribed GH therapy, there is a risk that they will not achieve the physical and psychological benefits of treatment [120]. Data suggest that poor concordance is frequent among patients receiving GH therapy [119,121]. In another study 15–24% of 630 children missed more than three injections per month (Fig. 2) [118]. It is therefore important to consider non-adherence as a possible cause in all cases of treatment failure. Although complete non-adherence would be easy to detect by, for instance, cessation of growth in adolescents and children, less profound levels of non-adherence are more difficult to recognize. 6.2. Key factors affecting adherence to therapy Major factors associated with non-adherence include underestimating the consequence of missing doses, dissatisfaction with treatment results, perhaps due to unrealistic expectations, injection

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Fig. 2. Relationship between treatment compliance (missed injections) and 6- and 12-month height velocity (annualized). From Desrosiers P et al. Patient outcomes in the GH Monitor: the effect of delivery device on compliance and growth. Pediatr. Endocrinol. Rev. 2 Suppl 3 (2005) 327–331. Reproduced with permission [118].

discomfort, patient choice of delivery device and inadequate training in device technique [119,122,123]. It should be recognized that achieving full adherence in pediatric patients requires not only the child's cooperation but also devoted, persistent and adherent parents. Additional challenges are encountered when the child reaches adolescence because of the corresponding developmental need for disengagement from the parents. Technical and physical factors associated with the ease of administration can have a major impact on treatment adherence. Frequent dosing, particularly of long-term treatment, and medications that are difficult to prepare and administer could also be anticipated to be associated with poor adherence because of potential for errors in dilution and mixing [124]. In one study, a liquid formulation of GH was preferred by 98% of study participants over a freeze-dried preparation that needed reconstitution. Patients reported that the liquid formulation was less time-consuming, easier to inject and more convenient [125]. Data from other studies support patient preference for a liquid formulation [126,127], as this is associated with less pain following injection. Long-term administration of a treatment that is associated with discomfort and pain could be expected to exert a negative impact on treatment acceptance and ultimately to reduce patient adherence [128,129]. Injection pain may be caused by lack of tolerability to the drug formulation, injection volume and the site of injection [130]. Elements of the drug's formulation that may affect injection site pain include the pH, choice of preservative, tonicity and buffer [131,132]. Preservatives, present in solutions of drugs for multiple injections, are needed to protect the drug from microbial degradation or contamination [133]. GH preparations containing phenol (3 mg/mL) as a preservative are reported to be associated with less injection site pain than preparations containing benzyl alcohol, a commonly used preservative [132]. The buffer used to maintain the pH of a drug formulation within a narrow range may also affect the experience of pain on injection. Citrate and histidine are commonly used as buffering agents, with patients reporting increased injection pain with citrate compared with histidine [132,133] (Fig. 3).

Fig. 3. Perception of pain at time = 0 min after injection of histidine vs citrate solutions (upper panel), and histidine vs saline (lower panel) [132]. Reproduced from Laursen T, Hansen B, Fisker S. Pain perception after subcutaneous injections of media containing different buffers. Basic Clin Pharmacol Toxicol 2006; 98 (2):218–221, with permission from John Wiley & Sons, Inc.

children as self-injection in childhood, contributing to the child's feeling of autonomy, increases the likelihood of long-term adherence to treatment. In a questionnaire survey, patients and physicians rated device reliability as the most important attribute of a GH injection device, closely followed by ease of use (Fig. 4) [129]. Lack of pain was considered by patients to be the third most important attribute for an injection device. Ease of use is particularly important when the device is being used by a child or adolescent. A device with only a few steps in preparation and with straightforward dose adjustment will be simple to use. The advantage of being able to store the GH preparation at room temperature [135] in a multi-dose pen injection system could therefore be expected to have a positive beneficial effect on treatment

6.3. Injection devices: impact on treatment adherence Previous research has documented that patients want GH administration devices that are easy to use and require few steps for successful administration [129]. Adherence to GH therapy is reported to be greater in those who self-inject (p b 0.01) and who use an automatic pen device compared with those who use conventional or prefilled syringes (p b 0.05) [134]. This supports the theory that the ease of use of technical interventions generally improves adherence. This physical aspect of treatment is likely to be particularly important in

Fig. 4. Mean scores for the five most important device attributes as assessed by study participants. Each attribute was ranked from 0 (not at all important) to 10 (extremely important) [129]. Reproduced from Dumas H et al. Understanding and meeting the needs of those using growth hormone injection devices. BMC Endocr. Disord. 6 (2006) 5 © BioMed Central.

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adherence due to enhanced convenience and the ability to support an active lifestyle. 7. Summary GH therapy in short-statured children born SGA or with TS or NS improves height SDS from baseline values, placing them within the normal range during childhood when treatment is started early enough in development. Evidence from long-term studies in SGA, TS and NS suggest that there is also a marked improvement in adult height. Additional benefits of GH therapy, including improved body composition, metabolic status, bone density and psychosocial profiles have also been reported. Objective assessment of prescription data has, however, revealed a high prevalence of poor adherence to GH therapy. For pediatric patients, poor adherence may result in a reduction in height velocity and, ultimately, in a lower than hoped for adult height. Enhancing patient adherence is therefore of utmost importance to the successful outcome of GH therapy. The inverse relationship between difficulty of administration and treatment adherence is one important aspect that should be taken into consideration. In this respect the availability of a prefilled, multi-dose injection device might have a positive beneficial effect on the likelihood of patients adhering to treatment regimens. Conflict of interest Anne-Marie Kappelgaard is employed by Novo Nordisk and has shares in the company. Torben Laursen has no conflict of interest disclosures. Acknowledgments The authors would like to thank Penny Butcher, Watermeadow Medical, UK (supported by Novo Nordisk) for her assistance in preparation of the manuscript. References [1] T.A. Wilson, S.R. Rose, P. Cohen, et al., Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee, Update of guidelines for the use of growth hormone in children: the Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee, J. Pediatr. 143 (2003) 415–421. [2] R.I. Horwitz, S.M. Horwitz, Adherence to treatment and health outcomes, Arch. Intern. Med. 153 (1993) 1863–1868. [3] P.E. Clayton, S. Cianfarani, P. Czernichow, G. Johannsson, R. Rapaport, A. Rogol, Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society, J. Clin. Endocrinol. Metab. 92 (2007) 804–810. [4] J. Karlberg, K. Albertsson-Wikland, Growth in full-term small-for-gestational-age infants: from birth to final height, Pediatr. Res. 38 (1995) 733–939; (Erratum in:), Pediatr. Res. 39 (1996) 175. [5] J. Leger, C. Levy-Marchal, J. Bloch, et al., Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study, BMJ 315 (1997) 341–347. [6] J. Leger, C. Garel, A. Fjellestad-Paulsen, M. Hassan, P. Czernichow, Human growth hormone treatment of short-stature children born small for gestational age: effect on muscle and adipose tissue mass during a 3-year treatment period and after 1 year's withdrawal, J. Clin. Endocrinol. Metab. 83 (1998) 3512–3516. [7] J.P. Karlberg, K. Albertsson-Wikland, E.Y. Kwan, B.C. Lam, L.C. Low, The timing of early postnatal catch-up growth in normal, full-term infants born short for gestational age, Horm. Res. 48 (Suppl. 1) (1997) 17–24. [8] A.C. Hokken-Koelega, M.A. De Ridder, R.J. Lemmen, H. Den Hartog, S.M. De Muinck Keizer-Schrama, S.L. Drop, Children born small for gestational age: do they catch up? Pediatr. Res. 38 (1995) 267–271. [9] P. Polo Perucchin, C. Traggiai, M.G. Calevo, et al., Auxological and metabolic study in small for gestational age children during 2 years follow-up, J. Matern.Fetal Neonatal Med. 24 (2011) 381–387. [10] N. Baena, C. De Vigan, E. Cariati, et al., Turner syndrome: evaluation of prenatal diagnosis in 19 European registries, Am. J. Med. Genet. A 15 (2004) 16–20. [11] E.B. Hook, Spontaneous deaths of fetuses with chromosomal abnormalities diagnosed prenatally, N. Engl. J. Med. 299 (1978) 1036–1038.

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