Growth Hormone In Children Research Articles

Inhaled Growth Hormone (GH) Compared with Subcutaneous GH in Children with GH Deficiency: Pharmacokinetics, Pharmacodynamics, and Safety

Delivery of GH via inhalation is a potential alternative to injection. Previous studies of inhaled GH in adults have demonstrated safety and tolerability. We sought to assess safety and tolerability of inhaled GH in children and to estimate relative bioavailability and biopotency between inhaled GH and sc GH. This pediatric multicenter, randomized, double-blind, placebo-controlled, crossover trial had two 7-d treatment phases. Patients received inhaled GH and sc GH in the alternate phase. Placebo was administered by the route opposite from active drug. GH and IGF-I levels were measured at multiple time points. Pharmacokinetics were assessed using noncompartmental methods. Twenty-two GH-deficient children aged 6-16 yr were treated. Absorption of GH appeared to be faster after inhalation with maximum serum concentrations measured at 1-4 h compared with 2-8 h for sc GH. Mean relative bioavailability for inhaled GH was 3.5% (90% confidence interval 2.7-4.4%). Mean relative biopotency, based on IGF-I response, was 5.5% (confidence interval 5.2-5.8%). Similar dose-dependent increases in mean serum GH area under the curve and IGF-I changes from baseline were seen after inhaled and sc GH doses. Inhaled GH was well tolerated and preferred to injection. No significant changes in pulmonary function tests were seen. In this first pediatric trial of GH delivered by inhalation, it was well tolerated and resulted in dose-dependent increases in serum GH and IGF-I levels. This study establishes that delivery of GH via the deep lung is feasible in children.

Use of Recombinant Human Growth Hormone in Children with Thalassemia

Background: Growth failure occurs in children with chronic anemias and, in particular, in approximately 30% of those with thalassemia. Methods: We assessed recombinant human growth hormone (rhGH) use in a large cohort of children with thalassemia enrolled in the Pfizer International Growth Study Database (KIGS). Results: We identified 147 short children with thalassemia who were treated with rhGH in KIGS. Of these, approximately 40% had a primary diagnosis of GH deficiency (GHD). They had low birth weight, short parents, reduced genetic height potential, low insulin-like growth factor I levels and delayed bone age. Treatment with rhGH for 1 year resulted in a significantly increased growth rate regardless of underlying GH or pubertal status. Although the resultant growth rates for thalassemic children were significantly higher than at baseline, they were less than those seen in similarly treated short children with or without GHD. Conclusions: GH testing should be performed in short thalassemic children, and those with GHD should be treated with rhGH. The value of rhGH therapy in short thalassemic children without GHD is less clear-cut and requires further study regarding final height outcome.

Glucagon Stimulation Test for Childhood Growth Hormone Deficiency: Timing of the Peak is Important

In the glucagon stimulation test (GST) growth hormone (GH) secretion is considered sufficient when at least 1 value is >10 ng/mL. Because GH typically peaks at 90 or 120 minutes, we evaluated whether peak occurrence at other times ("atypical") signifies abnormal GH secretion. A retrospective review of 222 GSTs was conducted to determine these outcomes: 1) frequency of GH deficiency per confirmatory clonidine or arginine stimulation test in typical versus atypical GSTs, and 2) growth velocity standard deviation score (GVSDS) in patients with typical versus atypical GSTs. Of 222 tests, 57 GST results (25.7%) were atypical, and 54 GST results (24.3%) were deficient. Atypical deficient tests had a higher chance than typical deficient tests of predicting GH deficiency per confirmatory test (15/21, 71.4% versus 14/33, 42.4%; P < .05). Patients with deficient atypical GST results and sufficient confirmatory tests (n = 6) had a lower GVSDS than patients with deficient typical GST results (n = 18; -1.58 [-3.2-1.76], versus 0.23 [-1.54-3.95], P = .03). Overall, 75% of atypical deficient GST results were followed by atypical timing in a clonidine test. Three of the 222 tests (1.3%) peaked at 180 minutes. The GST can be terminated at 150 minutes without sacrificing sensitivity. A GH peak at a time other than 90 or 120 minutes may be a new important indicator of GH deficiency.

Obstacles to the prescribing of growth hormone in children with chronic kidney disease

Despite its effectiveness, recombinant human growth hormone (rhGH) is under-utilized in short children with chronic kidney disease (CKD). We conducted a multicenter study to explore the obstacles preventing children with CKD from receiving rhGH. We investigated the use of rhGH in 307 children with CKD from seven pediatric nephrology centers. Among the 110 patients who fell below the 5th percentile, 56 (51%) had not received rhGH. The most common reasons given for these children not receiving rhGH were family refusal, secondary hyperparathyroidism, and non-compliance. However, no explanation was apparent for 25% of the short children with CKD. Boys were more likely than girls to receive rhGH (65% vs 31%; P = 0.002). Use of rhGH was similar in African Americans and non-Hispanic Whites. Children who had received rhGH achieved a 0.5 increase in height z-score in the first year after the initiation of rhGH therapy. Children who had not received rhGH achieved a 0.03 increase in height z-score during the first year after falling below the 5th percentile (P = 0.005 vs the children who had received rhGH). Waiting for insurance company approval led to a significant delay in the initiation of rhGH treatment in 18% of patients. The fact that more than 50% of short children with CKD did not receive rhGH is secondary to multiple factors, many of which may be amenable to intervention efforts.

Cardiac Status after Childhood Growth Hormone Treatment of Turner Syndrome

In Turner syndrome (TS), GH treatment is well established. Data on cardiac status after discontinuation of treatment are scarce. This study aimed to assess biventricular size and function in TS at least 6 months after discontinuation of GH treatment. TS patients and healthy women prospectively underwent cardiac magnetic resonance imaging. Ventricular two-dimensional tomographic cine data were acquired to obtain biventricular volume, mass, and ejection fraction. Atrioventricular valve flow measurements were performed using a two-dimensional flow-sensitized sequence. Flow velocity curves were calculated and indices of biventricular diastolic filling were derived. Thirty-one patients [mean (sd) age 20 (2) yr, body surface area 1.75 (0.15) m(2), 5 (2) yr after GH discontinuation] and 23 normal control women [age 21 (2) yr, body surface area 1.80 (0.13) m(2)] were included. Compared with controls, patients had smaller mean end-diastolic volumes [right ventricle (RV), 84 (11) ml/m(2) vs. 79 (10), P = 0.02; left ventricle (LV), 81 (10) vs. 72 (9), P < 0.001], end-systolic volumes [RV 38 (7) ml/m(2) vs. 36 (6), P = 0.04; LV 34 (5) vs. 29 (4), P < 0.001], and stroke volumes [RV 46 (6) ml/m(2) vs. 43 (6), P = 0.03; LV, 47 (7) vs. 44 (4), P = 0.02]. Patients had a higher mean heart rate [79 (13) beats/min vs. 71 (10), P < 0.05]. Biventricular ejection fraction, mass, cardiac output, and diastolic filling pattern were comparable. After discontinuation of GH treatment TS patients showed no myocardial hypertrophy and well-preserved biventricular function. Ventricular volumes were smaller in Turner patients, compared with controls, whereas mean heart rate was higher. These last observations may be part of the natural development in TS and not linked to GH treatment, which at this point we consider safe.

Effect of growth hormone therapy on nitric oxide formation in cystic fibrosis patients

Airway nitric oxide production is decreased in cystic fibrosis. As growth hormone therapy has been shown to increase nitric oxide production in growth hormone-deficient patients, it may also affect nitric oxide production in patients with cystic fibrosis. The objective of the present study was to investigate the effect of growth hormone therapy on systemic and airway nitric oxide formation in patients with cystic fibrosis. Nitric oxide metabolites in serum and urine, amino acid concentrations in serum and sputum, as well as exhaled nitric oxide, were measured in children with cystic fibrosis before, during and after 1 yr of treatment with human growth hormone. Nitric oxide metabolite concentrations increased significantly in serum and urine during the treatment period. Serum amino acid concentrations (including l-arginine, the substrate for nitric oxide synthases) also increased during treatment. The systemic bioavailability of l-arginine for nitric oxide synthases, expressed as ratio of l-arginine/l-ornithine+lysine, remained unchanged. In contrast, l-arginine concentrations in sputum decreased significantly during growth hormone treatment, as did exhaled nitric oxide levels. Treatment with growth hormone in children with cystic fibrosis decreases exhaled nitric oxide by reducing the concentration of l-arginine in the airways.

Opgroeien met een korte gestalte: een pleidooi tegen plastische endocrinologie

In the Netherlands, growth hormone treatment in healthy children with short stature is still under debate. In this article we plead against widespread use of growth hormone in children with idiopathic short stature. From empirical studies it can be concluded that being short does not necessarily lead to psychosocial problems, that a considerable part of the children with idiopathic short stature remain short after hormone treatment, and that there are no evidence based positive effects of hormone treatment on psychosocial functioning. The discussion about plastic endocrinology also encompasses ethical considerations. Although hormone treatment to enhance short stature fits the broad aim of medicine, it still can be questioned whether this is the most appropriate intervention in these children. When psychosocial problems in short children are caused by social factors such as teasing or juvenilization, it can be argued that interventions should be directed primarily at the immediate environment of short individuals and at society. The use of hormone treatment may strengthen the opinion in society that short stature is a deviation problem that should and could be fixed, which in turn may lead to increased pressure for parents and children to choose hormone treatment. Moreover, treatment of the shortest 3% of the population can never eliminate short stature from society. Making a decision for this treatment in an individual child is a matter of weighing the pros and cons. Whatever the result of the decision process will be, it is recommended to improve psychosocial adjustment by focusing on other factors than height alone.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Metabolic and Respiratory Effects of Growth Hormone in Children With Cystic Fibrosis

Positive effects of growth hormone therapy on growth, nutritional status, and lung function have been observed in patients with cystic fibrosis, but the current evidence is based on unblinded studies that involved a small number of patients. This trial was designed as a multicenter, randomized, placebo-controlled, double-blind study to assess the efficacy and safety of 2 dosages of growth hormone in cystic fibrosis. Sixty-three dystrophic patients with cystic fibrosis were randomly assigned for 24 weeks to 1 of 3 treatment arms: growth hormone dosage of 0.11 IU/kg body weight per day, growth hormone dosage of 0.21 IU/kg body weight per day, or placebo. The 24-week double-blind period was followed by an open treatment period of 24 weeks. The primary outcome measure was the change in forced expiratory volume in 1 second in percentage predicted from baseline. Secondary outcome measures were changes in height, weight, and exercise tolerance. Height, growth velocity, and growth factors (insulin-like growth factor 1 and insulin-like growth factor-binding protein 3) increased significantly in both treatment groups, whereas weight gain did not differ between the growth hormone groups and placebo. A trend toward improvement in absolute forced vital capacity was observed in patients who received the higher growth hormone dosage, whereas forced expiratory volume in 1 second did not change significantly with growth hormone treatment. Maximal oxygen uptake during peak exercise increased significantly in treated patients. There were no significant differences in the frequency or severity of adverse effects or in the incidence of abnormalities in glucose metabolism. These data suggest that in the group investigated, growth hormone therapy was well tolerated and had positive metabolic effects but did not result in short-term improvement of lung function in patients with cystic fibrosis.

Twenty Years of Recombinant Human Growth Hormone in Children: Relevance to Pediatric Care Providers

Recombinant human growth hormone has revolutionized the management of children and adolescents with growth hormone deficiency and other growth disorders, but clinical and ethical controversies remain regarding diagnostic approach, optimal recombinant human growth hormone dose and duration, and expected outcomes. Management of pubertal and transitioning patients with growth hormone deficiency has also commanded increased attention. Recent clinical studies that demonstrate the positive health benefits of recombinant human growth hormone in children with cystic fibrosis, inflammatory bowel disease, and juvenile rheumatoid arthritis have not yet clarified issues about patient selection and appropriate long-term use. An understanding of current recombinant human growth hormone indications and controversies can facilitate patient evaluation and expedite referral for potential treatment. This review summarizes current indications for recombinant human growth hormone use, discusses clinical challenges, and provides recommendations for pediatricians caring for children who may be appropriate candidates for recombinant human growth hormone therapy.

The Genomic Approach to Growth Prediction

Background: A major objective when using recombinant human growth hormone (rhGH) in childhood is to attain the maximum sustained growth response that can be achieved in an individual child while avoiding adverse events and ensuring that biomarkers of response, such as insulin-like growth factor I (IGF-I), remain within acceptable limits. Conclusion: In practice, this is currently achieved by titrating GH dose against growth rate and serum IGF-I concentration.

Recombinant growth hormone for children and adolescents with Turner syndrome

Turner syndrome (TS) affects about one in 1500 to 2500 live-born females. One of the most prevalent and salient features of the syndrome is extremely short stature. Untreated women are approximately 20 to 21 cm shorter than normal women within their respective populations. Recombinant human growth hormone (hGH) has been used to increase growth and final height in girls who have Turner syndrome. To assess the effects of recombinant growth hormone in children and adolescents with TS. MEDLINE, EMBASE, The Cochrane Library, LILACS, BIOSIS, Science Citation Index and reference lists were used to identify relevant trials. Randomised controlled trials were included if they were carried out in children with TS before achieving final height. Growth hormone had to be administered for a minimum of six months and compared with a placebo or no treatment control condition. Two reviewers assessed studies for inclusion criteria and for methodological quality. The primary outcomes were final height and growth. Secondary outcomes included bone age, quality of life, cognitive performance, and adverse effects. Four RCTs that included 365 participants after one year of treatment were included. Only one trial reported final height in 61 treated women to be 148 cm and 141 cm in 43 untreated women (mean difference (MD) seven cm, 95% CI 6 to 8). Short-term growth velocity was greater in treated than untreated girls after one year (two trials, MD three cm per year, 95% CI 2 to 4) and after two years (one trial, MD two cm per year, 95% CI 1 to 2.3). Skeletal maturity was not accelerated by treatment with recombinant growth hormone (hGH). Adverse effects were minimally reported. Recombinant human growth hormone (hGH) 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. Additional trials of the effects of hGH carried out with control groups until final height is achieved would allow better informed decisions about whether the benefits of hGH treatment outweigh the requirement of treatment over several years at considerable cost.

The Multiple Indications for Growth Hormone Treatment of Pediatric Patients

GH has many approved uses in pediatric patients including GH deficiency, CRF, Turner syndrome, Prader-Willi syndrome, SGA, and ISS. The child should have an appropriate evaluation for poor growth and endocrine consultation as dictated by clinical and investigative findings. Treatment of the child with GH deficiency is universally accepted. Treatment of children with Turner syndrome is dependent on the child's growth and stature with early diagnosis and treatment offering the most favorable outcome. Prescription of GH for PWS patients should be done cautiously given the possible association between GH use and sudden death; further studies are needed to fully delineate such a relationship. If a child has a history of SGA and is below the 3rd percentile at age 2, endocrine referral should be considered. Adult heights within the normal range may be attained in SGA patients treated with GH. An individualized approach to children with ISS should be practiced. The clinician should take into consideration factors such as psychosocial concerns and must exclude alternative etiologies of poor growth prior to consideration of therapy with GH. For all etiologies, greater height gains generally have been shown to be associated with younger age at time of diagnosis and treatment. There are ethical, economic and psychosocial issues surrounding GH use in children such that sound clinical practice should include an individualized approach to any patient who may be a potential candidate for GH treatment.

Growth hormone therapy—established uses in short children

AbstractSince the first reported efficacious use of human growth hormone in 1958, numerous children have been treated with this hormone. This review discusses the five indications for use of human growth hormone in children that have been approved to date by the United States Food and Drug Administration. Conclusion: Further, long‐term studies will be needed to address the optimal use of this hormone in each of these conditions.

Growth hormone therapy—established uses in short children

Since the first reported efficacious use of human growth hormone in 1958, numerous children have been treated with this hormone. This review discusses the five indications for use of human growth hormone in children that have been approved to date by the United States Food and Drug Administration. Further, long-term studies will be needed to address the optimal use of this hormone in each of these conditions.

Use of growth hormone in children

The introduction of recombinant DNA-derived human growth hormone (rhGH) in the mid-1980s allowed studies to be undertaken in a number of growth disorders other than the classic indication--growth-hormone deficiency (GHD). In patients with GHD, optimizing the dose and frequency of rhGH administration, and early instigation of therapy, has led to near-normalization of final height. The use of rhGH in the treatment of Turner syndrome, Prader-Willi syndrome, intrauterine growth restriction, and chronic renal failure demonstrated the efficacy of therapy, although the increase in final height (5-7 cm) is less than that achieved in GHD. Cost-benefit implications need to be considered in the next phases of evaluating the role of rhGH therapy in these indications. To date, rhGH has only received approval for the management of idiopathic short stature in the US; as with the other wider growth indications, the lack of formal randomized, controlled trials hampers the full evaluation of efficacy, and a cautious approach should, therefore, be adopted for this particular indication. rhGH has a good safety record, although there are current concerns about the possible long-term increased risk of colonic and lymphatic malignancy, which will require monitoring through national cancer registries.

Current use of growth hormone in children

Since the advent of growth hormone(GH), children with a wide variety of growth disorders have received GH treatment. In GH deficiency(GHD), Turner syndrome, chronic renal failure, children born small for gestational age, Prader-Willi syndrome, and idiopathic short stature, the therapeutic effects and safety profile of GH are reviewed. GH therapy has been clearly shown to improve height velocity and final adult height in a variety of pediatric conditions in which growth is compromised irrespective of GHD. Early initiation and individualization of GH treatment has the potential to normalize childhood growth. The supra-physiological doses of GH have been shown to increase height velocity during childhood and final height in non-GHD conditions. Adverse events during GH therapy are uncommon and often not drug related. However continued surveillance into adult life is crucial, especially in children receiving supra-physiological doses or whose underlying condition increases their risk of adverse effects

Growth and growth hormone in children born small for gestational age

Growth and growth hormone in children born small for gestational age

Growth and growth hormone in children born small for gestational age

Although most children born small for gestational age catch up in growth by age 2 y, up to 14% remain more than 2 standard deviations below the mean for height. Recombinant growth hormone is approved by the US Food and Drug Administration and by the European Agency for Evaluation of Medicinal Products for the treatment of children born small for gestational age who fail to manifest catch-up growth by 2 y or 4 y, respectively. We conclude from clinical studies that growth hormone therapy can induce catch-up growth in these children.

Growth hormone for children with chronic renal failure and on dialysis

We studied all children with CRF who received recombinant human growth hormone (rhGH) for more than a year (mean+/-SD duration of therapy 3.7+/-2.5 years) over an 11-year period. There were 32 children. Twenty-one children were conservatively managed, with a mean glomerular filtration rate (GFR) of 24+/-12 mL min(-1)/1.73 m2 at the start of rhGH. Their height standard deviation score improved from -2.5+/-1.4 to -2.1+/-0.7 at 1 year (P=0.3), -2.0+/-0.7 at 2 years (P=0.01), and -1.6+/-0.6 at 3 years (P=0.001). After that there was no improvement. Eleven children were on dialysis, six on haemodialysis (HD) and five on peritoneal (PD). Ht SDS improved from -2.7+/-0.5 to -2.3+/-0.5 at 1 year (P=0.02). Thereafter there was no further improvement. RhGH was stopped because of transplantation in 29 patients at a mean+/-SD age of 12.1+/-4.0 years. Mean Ht SDS was -1.8+/-0.8 at transplant and there was no change over the following 5 years. In conclusion, treatment with rhGH resulted in improvement in Ht SDS in conservatively managed CRF for up to 3.0 years and for 1 year in children on dialysis. Discontinuation of rhGH after transplantation resulted in little change in Ht SDS.

The impact of idiopathic childhood‐onset growth hormone deficiency (GHD) on bone mass in subjects without adult GHD

Despite seemingly adequate growth hormone (GH) treatment during childhood, children with GH deficiency (GHD) have reduced bone mineral density (BMD) at final height. The aim was to evaluate BMD and bone mineral content (BMC) in adults treated for idiopathic childhood-onset (CO) GHD, 18 years after stopping GH treatment. Twenty-six (11 females) patients with idiopathic CO GHD participated. All patients but two had been treated for isolated GHD in childhood. The childhood diagnosis was established by an insulin tolerance test (ITT) and reassessed in adulthood by an ITT (N = 21) or arginine test (n = 5), revealing that 10 patients had GHD according to adult criteria. Accordingly, the patient group was divided into (1) patients who did not have persistent GHD in adulthood and (2) patients who did have persistent adult GHD. Twenty-six healthy subjects acted as age-, gender- and body mass index (BMI)-matched controls. The patients who did not have persistent GHD had significantly lower IGF-I values and whole-body, femoral neck and lumbar spine BMD compared to controls [0.994 +/- 0.10 vs. 1.114 +/- 0.11 g/cm2 (P = 0.003), 0.842 +/- 0.12 vs. 0.962 +/- 0.11 g/cm2 (P = 0.006) and 1.026 +/- 0.14 vs. 1.127 +/- 0.13 g/cm2 (P = 0.004), respectively]. Femoral neck BMD was significantly reduced in the patients who had persistent GHD, compared to controls (0.842 +/- 0.09 vs. 0.938 +/- 0.11, P = 0.04). Significant correlations were observed between all bone variables and IGF-I in all subjects, whereas no correlations were observed between bone variables and GH peak levels in the 26 patients. In conclusion, we found that (1) patients with idiopathic CO GHD, who at retest in adulthood did not have GHD according to adult criteria, had reduced serum IGF-I and BMD/BMC compared to controls. (2) This observation was also made in the patients who did have persistent GHD in adulthood. The findings may reflect the fact that the present diagnostic criteria for adult GHD (i.e. response to the ITT) do not reflect the clinical consequences of disordered GH-IGF axis in CO GHD young adults who were treated with GH in childhood. Alternatively, despite seemingly adequate GH treatment in childhood an optimal peak bone mass in adolescence may never have been reached in either of the groups. (3) IGF-I levels correlated with clinical signs of the adult GHD syndrome. We believe that further studies on the indications and diagnostic procedures for GH treatment after cessation of linear growth are necessary.