Long-term results with growth hormone therapy in idiopathic hypopituitarism

More than 30 years after its introduction, growth hormone (GH) treatment is well established in children with GH deficiency. Nevertheless, the long-term results of this therapy, expressed as height, are generally considered unsatisfactory. We report on results obtained in a group of GH-deficient children who were treated with daily injections of recombinant GH within the first 5 years of life and who reached an adult height very close to their target height. The full catch-up growth to the target height demonstrated in these patients suggests that replacement therapy should be started early and continued until adulthood. Height at onset of puberty is an important variable which might significantly influence the adult height. The significant and prolonged influence of birth weight on growth response to GH therapy underlines the important role of fetal growth in planning early treatment of GH-deficient children.     

Growth hormone normalises height, prediction of final height and hand length in children with Prader-Willi syndrome after 4 years of therapy

BACKGROUND: Based on the reported favourable effects of growth hormone (GH) treatment on growth and body composition in Prader-Labhart-Willi syndrome, we studied age dependency and the long-term effects on growth dynamics to elucidate the assumed hypothalamic GH deficiency. METHODS: We examined 23 children treated with hGH (24 U/m(2)/week) during a median of 4 (range 1.5-5.5) years; group 1: 10 young underweight (age 0.3-4.1 years), group 2: 8 prepubertal overweight (age 3.7-9.5 years) and group 3: 5 pubertal overweight children (age 9.0-14.6 years). RESULTS: After 4 years of therapy, height gain amounted to 1.8 SD; height (0.0 SD) and hand length (-0.2 SD) were normalised in the 2 prepubertal groups; in children above 6 years, height prediction approached parental target height. Weight for height rose in group 1 (to 0.64 SD) and decreased in group 2 (to 0.71 SD) to normal levels. Bone maturation of the pubertal children was too advanced to show a clear growth response to GH (height gain 0.42 SD). Even in this group, weight for height was reduced, but remained supernormal. CONCLUSION: Under exogenous GH, growth and body proportions are normalised in prepubertal children. With early institution of treatment, final height prediction reaches the parental target height range after 3 years. Such a growth-promoting effect of exogenous GH has so far only been described in children with GH deficiency.     

US experience in evaluation and diagnosis of GH therapy of intrauterine growth retardation/small-for-gestational-age children

The potential role of exogenous GH in treating short children born small for gestational age (SGA) has been discussed since the early 1960s. Pivotal studies in Europe during the last 10 years have shown that GH treatment of short children born SGA during childhood and early puberty (1) normalizes stature, (2) increases final height above predicted height and (3) allows children to reach their target height. A study now under way in the USA will provide additional much needed data about efficacy and safety of GH treatment in intrauterine growth retardation/SGA.     

Partial growth hormone deficiency (GHD) in children has more similarities to idiopathic short stature than to severe GHD

INTRODUCTION: Assessment of growth hormone (GH) secretion is based on stimulation tests. Low GH peaks in stimulation tests, together with decreased insulin-like growth factor-I (IGF-I) secretion, confirm a diagnosis of GH deficiency (GHD). However, limitations in interpreting the test results and discrepancies between GH and IGF-I secretion in particular patients have both been reported. GH therapy should improve the prognosis of adult height (PAH). The aim of the study was to compare the deficit of height at diagnosis, IGF-I secretion and PAH in children with either decreased (in varying degrees of severity) or normal GH secretion in stimulation tests. MATERIAL AND METHODS: The analysis comprised 540 short children (373 boys, 167 girls), aged 11.7 +/- 3.2 years. In all the patients two GH stimulation tests were performed, IGF-I serum concentration was measured, bone age was assessed and PAH was calculated. According to the GH peak in the two stimulation tests, the patients were classified into the following groups: severe GHD (sGHD)--GH peak < 5 ng/mL (n = 44), partial GHD (pGHD)--GH peak 5-10 ng/mL (n = 190), idiopathic short stature (ISS)--GH peak at least 10 ng/mL (n = 306). RESULTS: A significantly greater deficit of height, lower IGF-I secretion and worse PAH were observed in sGHD than in both remaining groups, while all the differences between pGHD and ISS in the parameters analysed were insignificant. CONCLUSION: The results obtained indicate the necessity of applying another methods of qualifying short children for GH therapy other than GH stimulation tests with a cut-off value at a level of 10 ng/mL.     

Transition care of patients with growth hormone deficiency from pediatric endocrinologists to adult endocrinologists

ObjectiveTo review whether growth hormone (GH) therapy should be continued into young adulthood, beyond achievement of final height, when GH deficiency persists, to summarize the recent evidence of the benefits of GH treatment during the transition period, and to address cur-rently debated issues involving diagnosis, treatment, and transition of care.MethodsPrimary literature was reviewed in the fol-lowing areas: the benefits and risks of GH therapy during the transition period, the diagnostic criteria for GH defi-ciency and recommended testing procedures during transi-tion, the optimal dose of GH therapy during transition, and the factors to consider in the transition of care from the pediatric to the adult endocrinologist.ResultsStudies support the continuation of GH therapy through the transition period until accrual of peak bone mass, rather than cessation of GH treatment when adult height has been achieved. Continued GH treatment in patients with persistent GH deficiency after achieving final height has been associated with significant additional bone maturation and improved overall metabolic profile. The selection of the most appropriate methods and cutoff val-ues for retesting GH deficiency during the transition period remains a challenge. Reassessment of the optimal GH dose is a key component of transition care.ConclusionFor patients with GH deficiency that will likely persist into adulthood, it is important to begin discussing possible continuation of GH treatment early in the management of GH deficiency. Clear communica-tion between pediatric and adult endocrinologists will be needed to determine the timing of the patient-care transi-tion and to minimize the interruption of GH therapy during the transition period. (Endocr Pract. 2012;18:256-268)     

Growth after radiotherapy and chemotherapy in children with leukemia or lymphoma.

The effect of radio- and chemotherapy on auxological parameters was investigated in 30 children treated for acute lymphatic leukemia (ALL) or non-Hodgkins lymphoma (NHL). Growth velocity was decreased during the first year of treatment. Catch-up growth was insufficient during the following years. Thus, the whole group experienced a loss of height of 0.49 +/- 1.1 SD at 6.8 +/- 2.6 years after diagnosis. Height and growth velocity were not different between children who received 18 or 24 Gy cranial irradiation; however, growth velocity was significantly lower in children who were treated for more than 2 years or who had the more intensive chemotherapeutic protocol. Evaluation of the growth hormone (GH) response to pharmacological stimulation revealed reduced GH peaks in 47% of the patients, but there was no correlation of GH peak with growth or treatment parameters. In conclusion, the impairment of growth in children after treatment for ALL or NHL might be related to the intensity and duration of chemotherapy.     

Skeletal dysplasia, growth hormone treatment and body proportion: comparison with other syndromic and non-syndromic short children

Skeletal dysplasias comprise a diverse group of conditions that usually compromise both linear growth and body proportions. It is of theoretical interest to evaluate the effect of GH treatment on linear growth, body proportion and final height in the different skeletal dysplasias. Reported experience of GH treatment in short children with skeletal dysplasia is sparse and often limited to short treatment periods and knowledge of its effects on final height and body proportion is generally lacking. Formal studies are almost all confined to achondroplasia as the most common entity. First-year response is typically a 2-3 cm increase in growth velocity in prepubertal children, or a gain of about 0.5 SDS or less in relative height from a baseline level of -4 to -5 SDS. GH treatment for up to 5 years in achondroplasia can produce a total height gain of about 1 SDS. Apart from achondroplasia, treatment of hypochondroplasia and dyschondrosteosis with GH has been reported in a small number of patients. Long-term data are, however, lacking. Of theoretical interest is that in many syndromic or non-syndromic short-statured children body proportion, i.e. trunk to leg length ratio, does not seem to be dependent on the degree of GH sufficiency and does not seem to be changed by GH treatment. GH treatment, at least in the prepubertal period, does seem to influence degree of disproportion.     

Pharmacological testing of growth hormone secretion

The laboratory confirmation of growth hormone (GH) deficiency (GHD) has been extensively studied. Multiple stimuli induce GH release, but insulin-induced hypoglycemia usually is considered the 'gold standard'. Seventy-five to 90% of normal children have significant increments of hGH to any single test. Complete and partial syndromes of GHD have been defined, but some patients with a clinical appearance of GHD release hGH during provocative testing. Discordant results on varied tests may occur in the same child. Sequential and simultaneous tests have been attempted with diverse time patterns; testing sequence may significantly affect data interpretation. Persistent problems with GH provocative tests remain: normal data not strictly defined throughout childhood, multiple tests with discordant results, and substantial discrepancies of immunopotency estimates with different radioimmunoassays. Some children with 'normal' hGH increments during provocative tests, despite clinical GHD, may require short-term treatment with hGH to finally establish the diagnosis.     

Growth and growth hormone in children after bone marrow transplantation

Growth and growth hormone (GH) were investigated every year in 24 children after allogeneic bone marrow transplantation (BMT) for severe aplastic anemia (SAA) or leukemia. Conditioning included total body irradiation (TBI) in all cases of leukemia. The young leukemic children grew poorly. At 4 years after BMT, the mean standard deviation score for attained height had decreased from 0 to -1.73. GH deficiency was diagnosed with provocation tests. Three years after BMT, 10/18 children had a subnormal response. Ten children were further investigated with 24-hour GH profiles. Children with SAA had normal growth and GH levels. TBI seemed to be the major factor responsible for impaired growth.     

Final height of growth hormone-treated GH-deficient children and girls with Turner's syndrome: the Dutch experience. The Dutch Advisory Group on Growth Hormone

In the Dutch growth hormone (GH) registration database there are currently 552 GH-deficient children being treated, subcutaneously, with recombinant human GH six to seven times per week. Of those, 112 who have been treated for at least 2 years have reached final height. Mean age at start of therapy was 11.70 years. Mean GH dose was 15.5 IU/m(2) body surface per week. Mean final height was 173.2 cm (boys) and 159.7 cm (girls) and -1.36 SD of the population mean. Of the patients, 73.2% and 63.4%, respectively, reached a final height above -2 SD of the population or within target limits. FH-SDS was higher compared with the results of earlier cohorts with different treatment regimens. Target height, GH peak value at diagnosis, age at start of GH therapy, height SDS (HSDS) at start of puberty, and duration of GH therapy were significantly correlated with final height. These results, combined with those of a prospective GH dose-response study, suggest that better long-term results can be obtained with early and prolonged treatment and if the GH dose is individually adapted to the short-term growth response. In an ongoing dose-response study, 68 girls with Turner's syndrome, aged 2-11 years, were randomized into three dosage groups with a daily GH dose of: (group A) 4 IU/m(2) body surface; (group B) 4 IU/m(2) in the first year of therapy and 6 IU/m(2) thereafter; (group C) 4 IU/m(2) in the first year, 6 IU/m(2) in the second year, and 8 IU/m(2) thereafter. After 4 years of GH therapy, girls aged 12 years or older started low-dose oestrogen therapy. After 7 years of GH therapy, mean HSDS in all three groups had increased to values above the third percentile for healthy girls. Mean final height and final height gain of 25 girls was 159.1 and 12.5 cm, 161.8 and 14.6 cm, and 162.7 and 16.0 cm in groups A, B and C respectively. These long-term and final height results are more favourable than the results of earlier Dutch Turner's syndrome studies. Possible explanations are the higher GH doses and/or the younger age at start of GH therapy.     

Growth hormone treatment in short Japanese children born small for gestational age

Recent reports have shown that high-dose growth hormone (GH) treatment in short children born with small for gestational age (SGA) resulted in a pronounced acceleration of linear growth. We describe the results of multicenter trials of recombinant human GH (rhGH) treatment in short SGA children in Japan. Two clinical studies were performed and the results were combined. Study 1 comprised 104 SGA children and study 2 comprised 61 SGA children. The patients were divided into three groups: group 1 consisted of 20 patients (13 boys and 7 girls) who received rhGH 25 microg/kg per day six or seven times per week in the first year and 50 microg/kg per day in the second year and thereafter; group 2 consisted of 48 patients (28 boys, 20 girls) who received rhGH 45/50 microg/kg per day; group 3 consisted of 44 patients (28 boys, 16 girls) who received 90/100 microg/kg per day. The mean increments in height SDS were 0.46, 0.67 and 0.94 SD in boys and 0.49, 0.79 and 0.93 SD in girls in groups 1, 2 and 3, respectively. The mean increment in height SDS at 2 years in group 3 was significantly greater than that in group 1, but it was not significantly different from that in group 2 in boys and girls. Our data demonstrated that high-dose GH administration significantly improved height velocity and height SDS in short SGA children. Additional studies are necessary to optimize a long-term GH treatment regimen and combined luteinizing hormone releasing hormone analog treatment for final height. Careful observation is also necessary to assess the metabolic effects of high-dose GH, especially on carbohydrate metabolism.     

Treatment of juvenile rheumatoid arthritis with growth hormone

Severe growth retardation and profoundly altered body composition are observed in children with juvenile chronic arthritis receiving glucocorticoids. This study assessed the effects of growth hormone (GH) on height velocity, body composition and bone density. Fourteen patients were treated with GH (1.4 U/kg/week) for 1 year and then studied for a 2nd year off GH. The treatment increased insulin-like growth factor 1 and insulin-like growth factor binding protein 3 plasma levels. All patients showed an increase in height velocity. Lean body mass increased by 12%. After the cessation of GH therapy, height velocity fell to pretreatment values, and weight and fat mass increased markedly. Bone formation and resorption markers significantly increased during treatment and returned to pretreatment values after discontinuation of GH treatment. These results suggest that GH may partially counteract the adverse effects of glucocorticoids on growth and metabolism in patients with chronic inflammatory disease.     

Stepping into adulthood: the transition period

The period of growth from late puberty to full adult maturation, termed the transition period, is important for tissue maturation. Peak bone mass, muscle mass and strength are usually attained in this period. However, it is common clinical practice in children with growth hormone deficiency (GHD) to discontinue growth hormone (GH) treatment in adolescence after attainment of final height. Therefore, patients with childhood-onset GHD that continues into adulthood and who do not receive treatment as adults may experience more severe consequences than patients who acquire GHD as an adult. Recent studies indicate that bone and muscle maturation are attenuated if GH treatment is discontinued at final height. Furthermore, these patients will also develop cardiovascular risk factors that are normally associated with GHD in adults. Much debate surrounds when retesting for GHD should be carried out and when GH treatment should be restarted in adolescents; many of these patients will not have severe GHD according to the criteria set for adults. The transition period is an appropriate time to modify GH doses. Finally, registries exist that have recorded clinical treatment experiences for children and adults. Tools that collect and analyse data provide an important opportunity to investigate issues related to transition.     

Growth hormone secretion during sleep. I. Comparison with GH responses to conventional pharmacologic stimuli in pubertal and early pubertal short subjects. Effects of treatment with human GH in patients with discrepant measurements of GH secretion

Growth hormone (GH) was measured in 215 short children (147 males and 68 females, 123 prepubertal, 92 at early pubertal stages), comparing GH responses to classical pharmacologic stimulation tests and spontaneous GH secretion during sleep. GH secretion during sleep, but not GH responses to stimuli, was higher in early pubertal than in prepubertal subjects. The patients were classified into five groups, according to the agreement between GH responses to stimuli and GH secretion during sleep: group I, normal GH-secreting children; group II, completely GH-deficient; group III, partially GH-deficient; group IV, with normal secretion during sleep and low responses to stimuli; group V, with the reverse situation. 30% of the patients were in groups IV and V, both at prepubertal and early pubertal stages. 46 patients of groups II-V were treated with extracted human GH(hGH). The growth rate was enhanced in groups IV and V, to the same extent as in groups II and III. Four points can be concluded: (1) the rise of GH secretion during sleep is an early event at the onset of puberty; (2) the discrepancy between the GH responses to classical stimuli and GH secretion during sleep are of pathological significance; (3) disturbances of GH secretion might be diagnosed by measuring GH secretion during sleep rather than by using conventional stimulation tests; (4) a trial course of hGH treatment could be proposed in patients with both kinds of discrepancies between GH responses to stimuli and GH secretion during sleep.     

Response to long-term growth hormone therapy in short children with reduced GH bioactivity

BACKGROUND/AIMS: The aim of the present study was to investigate whether short children with normal growth hormone (GH) immunoreactivity, but reduced bioactivity (bioinactive GH) could benefit from rhGH treatment as GH deficient (GHD) patients. Methods: We evaluated 12 pre-pubertal children (8 M, 4 F), with GH deficiency-like phenotype showing normal serum GH peak levels (>10 ng/ml), measured by immunofluorimetric assay (IFMA-GH), in contrast with a reduced GH bioactivity (bio-GH), evaluated using the Nb(2) cells. We also evaluated 15 age-matched GHD pre-pubertal children (11 M, 4 F) with serum GH peak <5 ng/ml. Both groups were treated with rhGH therapy at the dose of 0.23 mg/kg/week s.c. RESULTS: Serum bio-GH/IFMA-GH ratio at peak time for each patient during the provocative test was significantly lower in bioinactive GH than in GHD children (0.29 vs. 2.05, p = 0.00001). Recombinant human GH therapy induced a significant (p < 0.001) increase in growth rate in both groups during the first 2 years. In the third year of treatment, while growth rate in GHD children is maintained, in bioinactive GH patients it decreases remaining, however higher compared to the pre-treatment one. CONCLUSIONS: Short rhGH therapy given to selected bioinactive GH children improve growth rate and might result in greater final adult height.     

Effects of growth hormone treatment on cognitive function and head circumference in children born small for gestational age

Short stature is not the only problem faced by children born small for gestational age (SGA). Being born SGA has also been associated with lowered intelligence, poor academic performance, low social competence and behavioural problems. This paper summarizes the results of a randomized, double-blind, growth hormone (GH) dose-response study (1 or 2 mg/m2/day [ approximately 0.035 or 0.07 mg/kg/day]) on growth, intelligence quotient (IQ) and psychosocial functioning in 79 children born SGA at the start, and after 2 and 8 years of GH therapy, and addresses the associations with head circumference. Mean age at start of therapy was 7.4 years; mean duration of GH treatment was 8.0 years. In 2001, 91% of children born SGA had reached a normal height (> -2.0 standard deviation score [SDS]). Block-design s-score (Performal IQ) and Total IQ score increased (p < 0.001 for both indices) from scores significantly lower than those of Dutch peers at the start of therapy (p < 0.001) to scores that were comparable to those of Dutch peers in 2001. Vocabulary s-score (Verbal IQ) was normal at the start of therapy and remained so over time. Externalizing Problem Behaviour SDS and Total Problem Behaviour SDS improved during GH therapy (p < 0.01-0.05) to scores comparable to those of Dutch peers. Internalizing Problem Behaviour SDS was comparable to that of Dutch peers at the start of therapy and remained so, whereas Self-Perception improved from the start of GH therapy until 2001 (p < 0.001), when it reached normal scores. Head circumference SDS at the start of GH therapy and head growth during GH therapy were positively related to all IQ scores (p < 0.01), whereas neither were related to height SDS at the start of, or to its improvement during, GH therapy. A significant improvement in height and head circumference in children born SGA was seen after only 3 years of GH therapy, in contrast to randomized SGA controls. In conclusion, most children born SGA showed a normalization of height during GH therapy and, in parallel to this, a significant improvement in Performal IQ and Total IQ. In addition, problem behaviour and self-perception improved significantly. Interestingly, Performal, Verbal and Total IQ scores were positively related to head circumference, both at the start of, and during, GH therapy; head circumference increased in GH-treated children born SGA, but not in untreated SGA controls. These results are encouraging but also warrant confirmational studies and further investigations into the effects of GH on the central nervous system.     

Effect of different growth hormone dosages on the growth velocity in children born small for gestational age

To assess whether short-term growth hormone (GH) treatment can improve the linear growth in children who were born small for gestational age (SGA), we started a randomized multicenter trial in 26 age- and sex-matched prepubertal children born SGA. During the 1st year of GH therapy, all children received GH 0.23 mg/kg/week, then during the 2nd year, 13 children received the same dose (group A), and in the other 13 children, the dose of GH was doubled, i.e., 0.46 mg/kg/week (group B). During the 1st year of therapy, the growth velocity significantly (p<0.0001) increased in all patients. During the 2nd year, group A showed a significant decrease of the growth velocity (p<0.015), whereas group B maintained the growth rate. The height in group A children significantly increased during the 1st and the 2nd year of GH therapy (p<0.000002 and p<0.000001, respectively), reaching the normal range in 8 out of 13 children at the end of 2 years of GH therapy. The height in group B children significantly increased during the 1st and the 2nd year of GH therapy (p<0.000001 and p<0.000001, respectively), reaching the normal range in all 11 children who completed the GH therapy. The height gain was similar in groups A and B treated with the same GH dosage during the 1st year of therapy. A greater increase in height gain was found in children of group B treated with the higher GH dosage during the 2nd year of therapy as compared with group A (p<0.02). Significant increases in insulin-like growth factor I (p<0.0001), acid-labile subunit (p<0.0002), and bone/chronological age ratio (p<0.0001) were found after the 1st year of GH therapy, but no significant changes were observed during the 2nd year, independently of the GH dose. In conclusion, the height velocity of children born SGA significantly increases during the 1st year of GH therapy, diminishes, but can decrease during the 2nd year, if the GH dosage is not raised.     

Insulin-like growth factors as diagnostic tools in growth hormone deficiency during childhood and adolescence: the KIGS experience

Growth hormone (GH) deficiency in children covers a spectrum of disorders involving an impairment in GH secretion and a clinical syndrome characterized by permanent stunting of growth. Ascertaining impairments in GH secretion directly is complex, especially if GH deficiency (GHD) is isolated and not caused by congenital or acquired pituitary defects or genetic abnormalities. It has been established that the concentrations of GH-dependent peptides, such as insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3), are low in patients with GHD. Their levels are, however, also influenced by a multitude of factors, such as age, gender, height, liver function, nutritional status and other hormones. In addition, the type of complex formed, e.g. either binary or ternary, may influence the measurements of IGFs and their binding proteins. Therefore, levels of IGF-I and IGFBP-3 are generally lower in short children compared with age-matched norms. The reported diagnostic value of sub-normal basal levels of IGF-I and IGFBP-3 is, in terms of sensitivity and specificity, approximately 70%. Thus, definite proof of GHD can only be achieved by means of GH measurements. As the diagnosis of GHD is somewhat unlikely if IGF testing shows normal values, it is clearly advantageous to schedule these tests as part of the initial diagnostic work-up in short children, as their implementation is not only practical but also inexpensive. The Pfizer International Growth Database (KIGS) analysis of IGF-I (n = 2,750) and IGFBP-3 (n = 1,300) levels in children with idiopathic GHD shows that these two parameters are now firmly embedded in diagnostic strategies around the world.     

Growth hormone treatment does not alter lower limb asymmetry in children with Russell-Silver syndrome

BACKGROUND: Growth hormone (GH) treatment has been proven to have a beneficial effect on growth in children with Russell-Silver syndrome (RSS). METHODS: We describe 7 prepubertal children with RSS and lower limb asymmetry treated with GH for 3 years. RESULTS: There was a significant increase in height without any significant change in the asymmetry. CONCLUSIONS: We conclude that the rapid growth acceleration to GH treatment does not alter the lower limb asymmetry in children with RSS.     

Long-term evolution of endocrine disorders and effect of GH therapy in 35 patients with pituitary stalk interruption syndrome

We report long-term evolution of endocrine functions and the results of GH treatment in 35 patients (26 male and 9 female) with pituitary stalk interruption. At diagnosis, mean chronological age was 4.8 +/- 2.7 years, mean SDS for height -3.1 +/- 0.8 with a bone age retardation of 2.3 +/- 1.3 years and a mean SDS for growth velocity of -0.5 +/- 1.1; 80% presented complete GH deficiency (GHD) and 20% partial GHD; thyroid deficiency was present in 47.1% of children with complete GHD but absent in all partial GHD. Diagnosis was made during the first months of life in only 2 patients while 23% presented with severe neonatal distress; neonatal signs were only observed in the group with pituitary height below 2 mm (45.7% of patients). GHD was isolated in 40.6% of patients below 10 years while multiple hormone deficiencies was consistent at completion of growth in all patients. Height gain was significantly higher in patients who started GH treatment before 4 years (p = 0.002). GH treatment is very effective: in 13 patients, final height was -0.4 +/- 1.0, total height gain 3.2 +/- 1.2 and distance to target height -0.3 +/- 1.6 SDS.