| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Endocrine Care |
Department of Pediatrics (P.C.), University of California Los Angeles, Los Angeles, California 90095; Department of Pediatrics (A.D.R.), University of Virginia, Charlottesville, Virginia 22903; Department of Pediatrics (R.G.R.), Oregon Health & Sciences University, Portland, Oregon 97201; Novo Nordisk (G.M.B.), Princeton, New Jersey 08540; and Novo Nordisk (A.-M.K.), DK2830 Copenhagen, Denmark
Address all correspondence and requests for reprints to: Pinchas Cohen, M.D., Professor and Director of Research and Training, Division of Endocrinology, Department of Pediatrics, Mattel Children’s Hospital at University of California Los Angeles, 10833 Le Conte Avenue, MDCC 22-315, Los Angeles, California 90095-1752. E-mail: hassy{at}mednet.ucla.edu
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Today, about 100,000 children worldwide are treated with rhGH, but dosing remains largely arbitrary. In the United States, daily doses between 0.025 and 0.05 mg/kg per day are commonly used (4). The accepted daily dose in Europe varies between 0.025 and 0.035 mg/kg per day, and in Japan the common daily dose is 0.025 mg/kg per day or less (5). Although the growth response of children with GH deficiency to even low doses of GH may be dramatic, and clearly distinguishable from placebo, the potential benefits and risks of larger doses are unclear.
MacGillivray et al. and Kastrup et al. (6, 7) demonstrated that daily GH injections in GH deficiency provided a greater response to a three-times-a-week regimen. Retrospective analysis of the growth-promoting effects of GH in large postmarketing databases suggests that a linear relationship with dose may exist (8), but the nature of this relationship and the maximal effective dose have not been established. On the other hand, some uncontrolled studies did not demonstrate an effect of GH dose on adult height attainment (9). Thus, the lack of evidence-based practices regarding the dosing of GH in pediatric GH deficiency limits the treatment options available. Furthermore, current practice involves weight-based dosing and does not allow for optimization based on the response to therapy or other factors. Additionally, whereas a well recognized effect of gender on GH secretion (10) and possibly GH sensitivity (11) has been described in adults, the effect of gender on the response to GH in prepubertal children has never been explored.
In retrospective studies on healthy adults, serum levels of IGF-I and IGF binding protein-3 (IGFBP-3) have been correlated with the risk of developing prostate and premenopausal breast cancers later in life (12, 13). No direct causative effect of IGF-I on cancer development has been demonstrated, and the excessive risk seen was primarily in a subgroup of subjects with high IGF-I and low IGFBP-3 levels (14). The effects of GH dose apply to biochemical as well as to auxological parameters, and a concern has been raised recently that GH treatment may result in an unfavorable IGF-I risk profile in terms of cancer susceptibility (15).
In this large, randomized 2-yr study, we have addressed the dose-response relationship of GH with both auxological and biochemical parameters and examined these effects for gender differences and growth factor interrelationships.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
One hundred eleven GHD patients were enrolled (randomized), and 104 children completed the 2-yr trial. Seven children are not reported because final 2-yr heights were not available. Inclusion criteria mandated that GH deficiency was diagnosed, according to current practice, by a failure to achieve an adequate peak serum GH level in two GH provocative tests. These tests included stimulation with insulin, arginine, clonidine, or L-dopa, based on the standard of care in the specific institution. Serum GH was considered abnormal if peak levels in at least two tests were below 10 ng/ml in a polyclonal GH RIA (Endocrine Sciences, Inc., Calabasas Hills, CA) or 7 ng/ml in a monoclonal assay (Hybritech, San Diego, CA). All patients were prepubertal (Tanner stage I), with a bone age younger than 8 yr for girls or 9 yr for boys at the time of enrollment. All but 9 of the patients had isolated idiopathic GH deficiency, and all but 11 were Caucasian. All patients were naive to therapy with growth-promoting agents or sex steroids of any kind. Exclusion criteria included 1) the presence of any active tumor, active systemic disease states, chromosomal abnormalities or syndromic disease, and 2) chronic treatment with any medications other than thyroid or cortisol replacement. Twenty-two centers participated in patient recruitment, and no center enrolled more than 15% of the total patients. All centers obtained Institutional Review Board approval for the study, and written informed consent and assent were signed by all parents and their children.
Study design
Patients were randomized to receive either low (L)-dose rhGH (Norditropin) at a dose of 0.025 mg/kg per day given by a nightly sc injection, a medium (M) dose of 0.05 mg/kg per day, or a high (H) dose of 0.1 mg/kg per day. Gender, ethnicity, and etiology of GH deficiency were equally distributed among the three groups. The demographic, auxological, and biochemical data of the patients at the time of enrollment are detailed in Table 1
. Patients were seen by their physicians every 3 months. During each visit, a complete physical exam, including accurate height measurements by a Harpenden stadiometer and assessment of puberty, was performed, and blood was drawn for growth factor levels and a general laboratory safety panel. Height and height velocity SD scores were calculated using North American norms (16). Standard chemistry tests were performed at the local laboratory facilities of each institution. Bone age x-rays and measurements of hemoglobin A1c (HBA1c), fasting glucose, and fasting insulin levels were performed yearly. Bone age x-rays were read at a central radiology facility by a single senior radiologist who was blinded to the treatment group or the identity of the patient. Bone age was read according to the standards of Pyle et al. (17).
|
Concentrations of IGF-I in serum were measured by RIA as previously described (18). To avoid interference by serum IGFBPs, samples were chromatographed on a Sephadex G50 column with 0.25 M formic acid to separate the peptides from binding proteins. The RIA for IGF-I uses a rabbit antiserum (prepared by Drs. L. Underwood and J. Van Wyk, University of North Carolina, Chapel Hill, NC) distributed by the National Hormone and Pituitary Program. Concentrations of IGFBP-3 in serum were measured by an immunoradiometric assay manufactured by Diagnostic Systems Laboratories (Webster, TX), according to the manufacturer’s recommendations (19). IGF-I and IGFBP-3 SD scores were calculated from values obtained in a population of 400 normal children.
Statistical analysis
Data were entered into a central database and rechecked against the original study forms. The principal outcome measure of this study was the change in height after 2 yr of treatment. Additional outcome measures included change in serum IGF-I and IGFBP-3 concentrations and their SD scores, change in bone age and markers of carbohydrate metabolism, including fasting plasma glucose, HbA1c, and fasting plasma insulin. Potential effects of dose, length of treatment, and hereditary factors, including gender and parental heights, on these outcome measures were sought by forward stepwise regression analyses (Statistica, StatSoft, Tulsa, OK). Mean ± SD is shown in all cases. ANOVA and unpaired t tests were used to calculate differences among groups. P values of less than 0.05 were considered significant. The 
2 test was used to calculate differences in the rate of puberty among groups. The SD scores for IGF-I and IGFBP-3 were calculated after log-transformation.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Ninety-three percent of subjects experienced minor adverse events during the 2-yr trial (upper respiratory congestion, headache, otitis, pharyngitis, fever, rash, etc.), but the rates were not different among the three treatment groups. None of the events was considered related to GH therapy. No instances of pseudo-tumor cerebri, worsening scoliosis, leukemia, or slipped capital femoral epiphysis were reported. Three patients dropped out of the study for nonstudy-related issues. Anti-GH antibodies developed at low, clinically insignificant levels in 12% of the subjects, without relation to dose or growth response. General laboratory tests, including chemistry panels and erythrocyte sedimentation rate, did not display significant abnormalities at any point.
Dose-response effects of GH on auxology
All three GH doses resulted in a significant increase in growth velocity and growth velocity SD scores as seen in Fig. 1. The 0.05 and 0.1 mg/kg per day doses were significantly more potent in that regard than the 0.025 mg/kg per day dose during the first year of GH therapy. Similarly, as shown in Fig. 2, the height SD scores in the three groups rose substantially, with the low dose being significantly less efficacious than the two higher doses. Considering the results from boys and girls together, the two higher doses were very similar in their auxological effects over 2 yr and showed no statistical differences between each other. Bone age advancement occurred at a rate slightly higher than one bone age year per chronological year for each year of treatment and showed no effect of GH dose (Table 2). Because nearly two thirds of patients had a bone age less than 6 yr at the time the study started, there were not sufficient numbers to conduct an analysis of change in height prediction based on the Bayley-Pinneau method.
|
|
|
GH therapy induced an increase in IGF-I and IGFBP-3 levels and in their SD scores as seen in Figs. 3 and 4. Serum IGF-I levels rose more dramatically with the higher doses. More than 20% of patients displayed IGF-I values above the normal range for age and sex (SD scores > 2) regardless of dose, and the number of patients with elevated IGF-I levels was higher in the high-dose group, (at 2 yr, the actual number of patients with IGF-I SD scores above +2 were 4, 7, and 11 for L, M, and H, respectively).
|
|
) were above 1,000 ng/ml. These values were seen in patients from all three groups. Unlike the effect of GH on growth, the highest GH dose exhibited an incremental effect on growth factor levels, which was significant for the IGF-I SD scores. Interestingly, the IGF-I and the IGFBP-3 SD scores correlated best in untreated patients and in low-dose GH treatment (r = 0.55; P < 0.001), modestly in the medium-dose group (r = 0.4; P = 0.05), and not at all in the high-dose group. The relationship between growth and growth factor levels
The relationship between serum IGF-I and IGFBP-3 concentrations and growth, independent of the GH dose, are examined in Fig. 5. Both IGF-I (r = 0.33; P < 0.01) and IGFBP-3 (r = 0.32; P < 0.01) SD scores significantly correlated with the gain in height SD scores. Furthermore, dividing the patients into two groups by comparing those with the high vs. low IGF-I (or IGFBP-3) SD scores demonstrated that high IGF-I or high IGFBP-3 levels while on therapy predicted a greater growth response. Height SD score gained at 2 yr of therapy was evaluated in patients with the lower or upper half of the IGF-I and IGFBP-3 SD scores values at 12 months. The four cells, had 
height SD scores as follows: below the mean IGF-I SD scores and below the mean IGFBP-3 SD scores, 1.35 ± 0.66; below the mean IGF-I SD scores and above the mean IGFBP-3 SD scores, 1.87 ± 0.73; above the mean IGF-I SD scores and below the mean IGFBP-3 SD scores, 2.18 ± 0.98; and above the mean IGF-I SD scores and above the mean IGFBP-3 SD scores, 2.44 ± 0.85 (Fig. 6). The additive effect of IGF-I and IGFBP-3 SD scores on growth was significant by ANOVA and t tests (P < 0.05). There was no correlation between the gain in height SD scores and the IGF-I to IGFBP-3 ratio (data not shown).
|
|
Glucose and HbA1c were unchanged as a result of treatment in any group (Table 2). Fasting insulin concentrations by ascending GH dose group at baseline were 7 ± 5, 6 ± 4, and 7 ± 5 µU/ml (P = NS). At 12 months, these values had increased to 9 ± 6, 13 ± 9, and 15 ± 11 µU/ml, respectively. There was a dose effect for the development of fasting hyperinsulinemia due to GH treatment (P = 0.02 by ANOVA), but the difference was significant only for the low dose relative to the medium and high doses using t tests. At 24 months, these values had increased to 13 ± 9, 13 ± 8, and 17 ± 10 µU/ml, respectively (all P < 0.001 for dose group comparisons relative to baseline). There was a trend toward a dose effect for the development of fasting hyperinsulinemia due to GH treatment (P = 0.08 by ANOVA and by t tests comparing H to either L or M). These results are depicted in Table 2. The rise in fasting insulin concentrations was related to the rise in IGF-I (r = 0.4; P < 0.0001).
Analysis of outcome predictors
Using stepwise regression analysis models, we evaluated the contribution of various parameters to the growth response. The model for the 2-yr growth response, estimated by the gain in height SD scores, was analyzed. The model explained 52% of the variability in growth (r = 0.72). The most important predictor of growth was dose (partial r = 0.48). Other parameters explaining some of the variability in growth included entering puberty, gender, IGF-I at time zero, the height of the opposite gender parent, the bone age, and the rise in IGF-I.
The relationship between growth and gender
The great majority of the patients remained prepubertal throughout the study, and as shown in Table 2, there was no difference among males and females in this respect. Of those who entered puberty, bone ages were within the expected ranges (12 ± 2 yr for boys and 9.4 ± 2 yr for girls). Bone age advancement was not statistically related to gender. To further assess the role of gender in determining the response to GH, we separately plotted the height SD scores gained at 2 yr of therapy in male and female patients (Fig. 6A) and the increase in IGF-I SD scores (Fig. 6B). As Fig. 6A demonstrates, there is a linear dose-response curve for growth present in the boys, which is not seen in girls (or in the population as a whole). The mean 2-yr height increase in girls was 21 ± 5 cm. The 0.05 and 0.1 mg/kg per day doses were associated with a greater increase in height SD scores (2.6 ± 0.9 and 2.1 ± 0.9) than the 0.025 mg/kg per day dose (1.1 ± 0.9; P < 0.001 and P < 0.05, respectively). The mean 2-yr height increase in boys was 21 ± 5 cm. The change in height SD score in boys showed a graded increase in dose (1.4 ± 0.6, 1.9 ± 1.0, and 2.3 ±0.8 at 0.025, 0.05, and 0.1 mg/kg per day, respectively). When only prepubertal children were analyzed, similar results were observed (18 ± 3, 21 ± 5, and 24 ± 4 cm per 2 yr at 0.025, 0.05, and 0.1 mg/kg per day, respectively for males; and 17 ± 5, 25 ± 4, and 23 ± 5 cm per 2 yr at 0.025, 0.05, and 0.1 mg/kg per day, respectively, for females; P < 0.05 among all three groups for males, but only the 0.025 mg/kg per day group significantly different from the other groups for females). This indicates that the gender difference observed is not related to the occurrence of puberty. The IGF-I and IGFBP-3 SD scores displayed similar dose-response curves for each gender as observed for height gain (Fig. 6B; data not shown for IGFBP-3). IGF-I SD scores at baseline were -2.8 ± 0.9 for boys and -2.7 ± 0.6 for girls. The IGF-I SD score at 24 months was -0.5 ± 2 for boys and -0.7 ± 2 for girls. Overall, the 2-yr change in IGF-I SD score was 2.3 ± 1.6 for boys and 2.0 ± 1.8 for girls. The effects of dose and gender on the IGF-I SD score changes were similar to the dose and gender effects seen on height (Fig. 6B). When only prepubertal children were analyzed, similar results were observed (data not shown).
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
To date, only a few studies were performed to explore the optimal dosing strategy for GH in GH deficiency (22). Other studies retrospectively reviewed growth data and recommended the currently practiced dose over older protocols (23). Furthermore, retrospective analysis of large databases suggests a relationship between the adult height of GH-treated GHD children and the GH dose administered (24). Ongoing studies on the dose-response relationship between GH and growth of children with GH deficiency during puberty suggest that there is an incremental effect of increasing the dose from 0.03–0.07 mg/kg per day, but not to twice a day dosing (25). A recent study on pubertal GHD children (3) suggested that a GH dose of 0.1 mg/kg per day was more effective than a 0.05 mg/kg per day dose. However, that study had a very small number of females and was thus, essentially, a study of male GHD patients in puberty. The effects they observed are therefore similar to our results in boys.
Other indications for GH, including children with Turner’s syndrome, idiopathic short stature, chronic renal failure, and intrauterine growth retardation, provided opportunity for investigators to assess optimal GH dosing (26, 27, 28, 29), whereas other studies demonstrated that twice daily dosing in GH deficiency offers no further advantage in children with idiopathic short stature (30). Studies evaluating the response to GH in adults with GH deficiency demonstrated a dose-dependent effect on metabolic, body composition, and bone density parameters but also showed a strong relation between dose and side effects (31).
The adult height of GH-treated patients is influenced by the height gain attained during therapy, the rate at which bone maturation occurs, and the timing of puberty. Interestingly, there was no significant trend for faster bone age advancement or faster induction of puberty in the patients on the higher dose of GH in this study. This dispels concerns that high-dose GH might have deleterious effects on adult height through a mechanism that leads to a greater rate of bone age advancement (32).
GH induces the production of several components of the circulating IGF complex, including IGF-I and IGFBP-3 (33). These GH-dependent factors are diminished in GH deficiency and rise in the sera of GHD patients treated with GH, with clear evidence of a dose-response effect (34). In our study, growth, IGF-I SD scores, and IGFBP-3 SD scores were all significantly higher in the 50 µg/kg per day dose vs. the 25 µg/kg per day. We have shown that this dose-response effect of GH persists at the 100 µg/kg per day dose only for IGF-I (in boys), an effect that was similar to, but more pronounced than the growth response data. The IGFBP-3 SD scores were slightly and nonsignificantly higher in the high vs. medium dose. Half of the patients on the high-dose treatment had an IGF-I serum level outside the age-adjusted normal range, although no increase in side effects was noted. The actual IGF-I values observed in our prepubertal population were frequently in the pubertal range, but never outside the upper limit of normal for pubertal children.
Of particular interest is the observation that GH has a different dose-response curve for growth induction, IGFBP-3 generation, and IGF-I generation, with a saturation of the effect occurring first for growth, second for IGFBP-3, and last for IGF-I. In fact, our study suggests that a GH dose of 100 µg/kg per day is still within the linear range for IGF-I generation. Fortunately, it appears that the GH dose range associated with significant side effects in children is above the highest dose we used, because we observed no significant side effects with any dose.
The response to GH, measured as the cumulative height SD scores achieved at 2 yr of therapy, correlated with both the IGF-I SD scores and the IGFBP-3 SD scores during therapy (measured at 12 months). Similar results have been shown in nonrandomized trials (35). In fact, in our study, using both parameters together was a better predictor of growth than either one alone. Patients with higher growth factor levels (regardless of their GH dose) grew more rapidly. It is, therefore, attractive to speculate that the IGF-I level that is achieved by an individual patient, rather than his GH dose, determined the growth response. Although the serum IGF-I level may be a poor surrogate marker for tissue IGF-I (36), it may still serve as a tool for optimizing GH therapy. Controlled trials should address the role of serum IGF-I titration in the clinical management of GHD patients on GH therapy.
The relationship between the GH dose and GH side effects is evident in adults with GH deficiency (31, 37) but has not been observed in a vast clinical experience in children, in whom adverse events are rare and mostly idiosyncratic (38). We did observe a dose-dependent increase in the fasting insulin level, although no changes were observed in glucose or HbA1c. Hyperinsulinemia is a well recognized effect of GH (39), and although type 2 diabetes has been proposed as a rare side effect of GH therapy (40), most studies do not support a direct effect of GH on induction of diabetes. Nevertheless, the dose-response relationship between fasting insulin and the GH dose suggests that this parameter needs to be monitored in patients receiving higher doses of GH.
Recently, serum IGF-I levels have been reported to be associated with the risk of cancer of the prostate (12), breast (13), lung ( 41), and colon ( 14). However, the levels of IGFBP-3 in the sera of these patients appear to be protective. Thus, the effects of GH therapy, which raises both IGF-I and IGFBP-3 in sera, may not include increased cancer risk (42). Of particular interest is the observation that growth was optimal not in the patients with high IGF-I and low IGFBP-3, who presumably have the highest free IGF levels, but in the patients with high levels of both growth factors. This is in agreement with animal data suggesting that IGF-I plus IGFBP-3 promotes in vivo growth better than IGF-I alone (43).
Thus, it seems prudent to follow IGF-I and IGFBP-3 levels closely in patients treated with GH, even at standard doses, because our data indicate that nearly a third of patients (27% at 24 months of therapy) receiving GH at 0.05 mg/kg per day have IGF-I levels above the age-adjusted normal range. Furthermore, IGF-I levels correlated with the growth response, and patients with subnormal IGF-I levels tended to grow less rapidly, suggesting that they might have benefited from a higher IGF-I level, achieved perhaps with a higher GH dose. This is compatible with the recent recommendations of the Growth Hormone Research Society consensus guidelines statement on the diagnosis and treatment of GH deficiency in childhood and adolescence (44).
The optimal range of the IGF-I levels in GH-treated GHD patients is difficult to ascertain at this time. It is reasonable to expect prepubertal children in whom GH therapy is initiated to achieve substantial catch-up growth in the first 2 yr of treatment, and that high IGF-I levels (often at the +2 to 4 SD levels) may be required for this effect. Such a short period of IGF-I elevations appears unlikely to influence cancer risk later in life, especially considering the coelevations in IGFBP-3 (45). In patients who receive GH therapy for longer periods, however, IGF-I levels should probably be maintained within the normal range, as is the standard of care for adult GHD subjects (46).
The effects of gender on growth and the GH axis are substantial. Males and females have different mean heights throughout their life, undergo different growth spurts at the time of puberty (47), and have different GH secretion patterns as both adults and children (10, 48, 49). In general, females have higher GH secretion rates, which are due to both higher amplitude and higher frequency of the secretory pattern (50). In adults with GH deficiency, it has been shown that females display a lower responsiveness to standard GH doses (11, 51, 52). It has been suggested that both estrogen and androgen levels regulate this phenomenon (53). A possible connection to this observation is the finding that gender and sex steroids modulate the clearance of GH (54).
The effect of gender on the response to GH in prepubertal children has not been previously explored. In our study, gender differences in the responsiveness to GH in prepubertal children were observed. Surprisingly, males demonstrated a linear dose-response curve, with maximal effects at doses of 0.1 mg/kg per day, whereas girls showed a bell-shaped curve with a maximal effect at 0.05 mg/kg per day. The same gender dimorphism was shown for IGF-I responses. Previous studies in children indicate that sex steroid levels, although much lower than in adults, still display sexual dimorphism. In fact, E2 levels in prepubertal girls are 8-fold higher than in prepubertal boys (55), and T is higher in prepubertal boys relative to prepubertal girls (56). It is also recognized that body composition is different among male and female prepubertal children, a factor that could contribute to GH responsiveness (57). It has been suggested that even the low levels of these sex steroids that are found in children can modulate the GH axis. The higher GH levels and the lower GH response seen in females may represent a coordinated physiological manifestation of the different sex steroid milieu. Differences in body composition, in the form of larger fat mass and lower muscle mass in girls, could also contribute to the prepubertal differences in GH action that we observed (57). It has also been observed that prepubertal females, in addition to having greater fat to muscle ratio, display significantly higher serum GH binding protein levels than prepubertal boys (58). GH binding protein may temper GH action through sequestration. Similarly, leptin levels are higher in prepubertal girls than in prepubertal boys (56). It appears that gender differences are primarily at the level of GH sensitivity, because there are no significant differences between boys and girls when comparing the growth response as a function of the IGF-I level (data not shown). Our gender effect on GH responsiveness and the lack of a significant difference between the medium and high GH doses when both genders are taken into account, is important to consider in comparison with the report by Mauras et al. (3), who showed a significant difference between similar GH doses in GHD patients in puberty who were predominantly male.
Thus, our data suggest that optimization of GH therapy in children requires not only evaluation of auxological and biochemical responses but also consideration of the patient’s gender. In adults with GH deficiency, dosing strategies involving adjustment of the GH dose based on monitoring of IGF-I levels and clinical response are accepted and exhibit beneficial effects (34, 59, 60). The data from our study suggest that monitoring IGF-I levels (as well as IGFBP-3 levels) and consideration of these in an age- and gender-specific manner can help optimize GH therapy in children, as well (14, 42, 45). It is still not known, however, what IGF-I level would provide the optimal growth with minimal risks in pediatric GH recipients.
Outcome measures are multifactorial and show dependence on the dose of GH, but they are also dependent on the IGF-I response, temporal factors, and genetic parameters. Both the GH dose and IGF-I response are valid independent predictors of height outcomes, suggesting that they should be considered separately. However, dose was the primary predictor of height change in our study. This is the first time such a critical role for the GH dose has been noted. Dose is ranked low in the Kabi Pharmacia International Growth Study model (23) and not at all in the National Cooperative Growth Study report (61) or in a large Dutch study (62). The emergence of dose as a predictor of response in those studies may have been prevented by inclusion of a few subjects with high enough doses. We believe that the reason why the importance of the GH dose as a determinant of the growth response has only just begun to emerge is because our trial included the largest range of doses used to date and was the only true randomized, prospective, trial of its kind. Clearly, growth-promoting optimum doses are different by gender and are above the current usual recommended doses. Although it is premature to suggest changes in dose recommendations past the first 2 yr of treatment on the basis of our study, the results presented here are compelling in terms of the potential value of dosing as a tool for height optimization. We found that higher doses are safe; change in carbohydrate markers including fasting glucose and HbA1c did not occur, but may have been prevented by a compensatory rise in fasting insulin, indicating some degree of insulin resistance, which displayed a trend toward dose dependency. In view of our findings, we feel that herd dosing of rhGH is no longer appropriate. Outcomes depend on many factors, including the GH dose alone, and the choice of a GH dose based on weight alone ignores other factors directly affecting height outcomes.
Therefore, it seems logical to suggest that rather than exclusive weight based-dosing of GH in children, a new approach that takes into account the growth response, as well as changes in IGF-I and IGFBP-3 concentrations is needed. This approach should integrate these parameters into a dose adjustment algorithm that will result in individualized improvements in treatment results (59). Future studies, which will evaluate the utility of IGF-I monitoring and individual dose optimization, will determine whether these approaches will lead to better responses and fewer long-term complications.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Abbreviations: GHD, GH-deficient; H, high; HbA1c, hemoglobin A1c; IGFBP-3, IGF-binding protein 3; L, low; M, medium; rhGH, recombinant human GH.
Received January 24, 2001.
Accepted September 13, 2001.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  B. Bakker, J. Frane, H. Anhalt, B. Lippe, and R. G. Rosenfeld Height Velocity Targets from the National Cooperative Growth Study for First-Year Growth Hormone Responses in Short Children J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 352 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. F. Collett-Solberg, M. Misra, and on behalf of the Drug and Therapeutics Committee o The Role of Recombinant Human Insulin-Like Growth Factor-I in Treating Children with Short Stature J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 10 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. G Rosenfeld Pharmacogenomics and pharmacoproteomics in the evaluation and management of short stature Eur. J. Endocrinol., August 1, 2007; 157(suppl_1): S27 - S31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Cohen, A. D. Rogol, C. P. Howard, G. M. Bright, A.-M. Kappelgaard, R. G. Rosenfeld, and on behalf of the American Norditropin Study Group Insulin Growth Factor-Based Dosing of Growth Hormone Therapy in Children: A Randomized, Controlled Study J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2480 - 2486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Ali, M. Shim, E. Fowler, M. Greenberg, D. Perkins, W. Oppenheim, and P. Cohen Growth Hormone Therapy Improves Bone Mineral Density in Children with Cerebral Palsy: A Preliminary Pilot Study J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 932 - 937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. J. de Ridder, T. Stijnen, and A. C. S. Hokken-Koelega Prediction of Adult Height in Growth-Hormone-Treated Children with Growth Hormone Deficiency J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 925 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Bouhours-Nouet, F. Gatelais, F. Boux de Casson, S. Rouleau, and R. Coutant The Insulin-Like Growth Factor-I Response to Growth Hormone Is Increased in Prepubertal Children with Obesity and Tall Stature J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 629 - 635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Cohen Problems with Reclassification of Insulin-Like Growth Factor I Production and Action Disorders J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4235 - 4236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. O. Reiter, D. A. Price, P. Wilton, K. Albertsson-Wikland, and M. B. Ranke Effect of Growth Hormone (GH) Treatment on the Near-Final Height of 1258 Patients with Idiopathic GH Deficiency: Analysis of a Large International Database J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2047 - 2054. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Quigley, A. M. Gill, B. J. Crowe, K. Robling, J. J. Chipman, S. R. Rose, J. L. Ross, F. G. Cassorla, A. M. Wolka, J. M. Wit, et al. Safety of Growth Hormone Treatment in Pediatric Patients with Idiopathic Short Stature J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5188 - 5196. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
