0021-972X/91/730(M269$()3.00/0 Journal of Clinical Endocrinology and Metabolism Copyright (pi 1991 by The Kndocrine Society

Vol. 73, No. 6 Printed in U.S.A.

Growth Hormone (GH) Treatment in Short Normal Children: Absence of Influence of Time of Injection and Resistance to GH Autofeedback* JEAN-PIERRE CHANOINE, MAGDA VANDERSCHUEREN-LODEWEYCKX, MARC MAES, GENEVIEVE THIRY-COUNSON, MARGARITA CRAEN, AND GUY VAN VLIET Departments of Pediatrics, Universities of Brussels (JP.C, G.V.V.), Leuven (M.V.-L), Louvain (MM.), Liege (G.T.-C), and Ghent (M.C.), Belgium

ABSTRACT. Forty prepubertal subjects (25 boys and 15 girls) with idiopathic short stature, aged 3.8-14.6 yr, were randomly allocated to receive sc injections of recombinant human GH (hGH) 6 days/week at a dose of 3 IU (1.25 mg)/m2-day either in the morning or in the evening. After 6 months of therapy, each subject was switched over to the other schedule of injection. After 12 months, treatment was stopped, and the subjects were followed for 6 months. For the whole group, regardless of the time of injection, height velocity (centimeters per yr) was 4.3 ± 0.9 before hGH treatment, 8.3 ± 1.9 during the first 6 months of treatment, and 6.9 ±1.6 during the last 6 months of treatment. Thirty-three of 38 subjects (87%) who completed 12 months of therapy presented an increase in height velocity greater than 2 cm/yr. Two patients (5%) developed antibodies to hGH and were among the nonresponders. There was no significant difference in growth response according to the schedule of injections. GH-releasing hormone (GHRH) testing was performed before and after 6 and 12 months of hGH therapy. When the last hGH

A

SIDE from the ethical question of whether short but otherwise normal children should receive human GH (hGH) (1), many medical questions regarding this treatment remain unanswered. Importantly, does exogenous hGH inhibit endogenous GH secretion, and does this inhibition influence growth during and after hGH therapy? Since 80% of endogenous GH secretion occurs at night and is qualitatively and quantitatively normal in short normal children (2, 3), it would seem more rational to inject supplemental hGH in the morning so that it would add to the subject's own secretion instead of shutting it

Received January 29, 1991) Address all correspondence and requests for reprints to: G. Van Vliet, Research Center, Hopital Sainte-Justine, Montreal, Quebec, H3T 1C5 Canada. * Presented in part at the September 1990 Meeting of the European Society for Pediatric Endocrinology, Vienna, Austria. This work was supported in part by grants from the National Fund for Medical Research, Belgium (no. 3.0047.89 to M.V.-L. and no. 3.4518.85 to G.V.V.) and Eli-Lilly Belgium.

injection was performed 12 h before the GHRH test, there was a 36% decrease in the maximum GH response {P < 0.01) and a 33% decrease (P < 0.01) in the GH secretory area compared to those before therapy. When the last hGH injection was performed 24 h or more before the GHRH test, no significant differences were observed. Insulin-like growth factor-I levels were not significantly different when measured 12 or 24 h after hGH. During the 6 months after discontinuation of hGH therapy, catch-down growth was observed in 44% of the subjects. We conclude that the schedule of injection does not influence the growth response, which wanes after 6 months; this waning effect is not related to declining insulin-like growth factor-I levels or GH autofeedback, suggesting a peripheral mechanism. Likewise, the catch-down phenomenon after hGH is discontinued is not related to a persistent diminution of pituitary responsiveness to GHRH. (J Clin Endocrinol Metab 73: 1269-1275, 1991)

off. Comparative studies of morning us. evening injection in hypopituitary patients have shown that although the closest similarity to normal hormone and metabolite patterns is obtained by evening hGH injection (4), both schedules give similar results in terms of insulin-like growth factor-I (IGF-I) levels and growth rates (5). Similar studies in children with normal GH secretion have not been reported. Another aspect of hGH treatment of short normal children is to ascertain whether the changes in height velocity that may occur during hGH therapy are indeed due to hGH. Many recent studies have reported increases of 2 cm/yr or more in height velocity after 6-12 months of hGH therapy in some short, slowly growing children (review in Ref. 6). No single clinical or biological parameter identifies these responders. However, it has generally been found that the slower the pretreatment height velocity, the greater the percentage of responders. This observation raises the possibility that the increase in height velocity may be due in part to spontaneous variation (7), placebo effect, or regression 1269

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toward the mean (6) and makes it necessary to design such studies with periods of treatment interruption. In this prospective study we followed the growth of a heterogenous cohort of children with short stature and normal GH response to pharmacological stimulation before and during 1 yr of hGH therapy, followed by a 6month interval without hGH. The specific goals of this study were to evaluate 1) the effect of the time of injection (morning us. evening) of exogenous hGH on the growth response; 2) the effect of exogenous hGH on the GH response to GHRH at various times after the last hGH injection; and 3) the evolution of growth parameters after hGH treatment is discontinued.

Subjects and Methods Study protocol Forty children with short stature were selected during a 12month period. The protocol was approved by the ethical comittees of the participating institutions, and written informed consent was obtained from the parents. Inclusion criteria were as follows: height less than 2 SD, chronological age greater than 3 yr, bone age less than or equal to chronological age, bone age less than 10 yr in girls and less than 12 yr in boys, height velocity below the 25th percentile for bone age (8), genitalia or breast stage 1 (9), and GH response greater than 10 yug/L to either a glucagon or an insulin stimulation test (10) performed within 12 months of starting hGH therapy. Exclusion criteria included previous hGH therapy; history of chronic disease; abnormal liver, renal, or thyroid function tests; diabetes mellitus; hypopituitarism; and chromosomal abnormalities. Pretreatment height velocity was assessed by the investigators during a 6- to 12-month observation period with at least three height measurements separated by a minimum of 3 months. The patients were then randomized to either morning (0700-0900 h) or evening (1900-2100 h) injection of hGH (Humatrope, Lilly Laboratories, Indianapolis, IN) at a dose of 3 IU (1.25 mg)/m2-day, sc, 6 days a week; after 6 months of therapy, each subject was switched over to the other schedule of injection, and the dose was adjusted to the body surface area attained. After 12 months, treatment was stopped, and the subjects were followed during 6 months without therapy. The subjects were followed every 3 months for the 18 months of the trial. A complete interim history and physical examination were carried out at each visit. Height, weight, and pubertal stage were recorded. An increase in growth velocity of at least 2 cm/yr after 1 yr of therapy was considered a positive response. Catch-down was defined as a height velocity between 12-18 months less than pretreatment height velocity minus 0.5 cm (to account for the normal growth deceleration that occurs over time in prepubertal children). The following investigations were performed on inclusion and after 6 and 12 months of hGH therapy: IGF-I, hGH and Escherichia coli protein (ECP) antibodies, a GHRH stimulation test (0.5 MgAg. iy> Somatorelin, Labaz-Sanofi, Brussels, Belgium), bone age, blood chemistry and hematology panels, thyroid function tests, testosterone (boys), and estradiol (girls).

JCE & M • 1991 Vol 73 • No 6

Pubertal stage was defined according to the criteria of Tanner (9). Height was obtained by averaging three measurements performed by the same physician with a Harpenden stadiometer, and height velocities were calculated as centimeters per yr. Weight was expressed as a percentage of median weight for height age according to the method of Tanner et al. (11). Bone age was measured by a single examiner (J.P.C.) using the RUSTW II method of Tanner et al. (12). Predicted height was calculated according to the method of Tanner et al. (13). The characteristics of the subjects at inclusion are described in Table 1. All but two subjects had a birth weight appropriate for gestational age. In spite of an increase in height velocity, two subjects were lost to follow-up after 6 months of therapy. Finally, two pubertal subjects did not return at the follow-up visit 6 months after discontinuation of hGH therapy. Methods All GH determinations during the GHRH tests were performed in the same laboratory using a previously described method (10, 14). To analyze the GH-releasing hormone (GHRH) tests, baseline GH values were obtained by averaging the values obtained 30 min before and at the time of GHRH injection. The maximum GH response was defined as the increment above the baseline value. The GH secretory area was calculated by trapezoidal integration between 0-120 min. All GHRH tests started between 0700-0900 h. Because some subjects omitted the hGH injection on the day before the GHRH test, the tests during treatment were performed 12, 24, or 36 h after the last hGH injection. The results of GHRH tests performed at 6 and 12 months were compared to the results of the initial GHRH test. IGF-I was measured by RIA after acidethanol extraction according to a previously described method (15). Antibodies to hGH were assayed independently at Lilly Laboratories, using polyethylene glycol separation (16), and at the Catholic University of Leuven, using dextran-coated charcoal separation. ECP antibodies were measured according to the method described by the hGH manufacturer (Dr. Sportsman, Lilly Laboratories). Statistics Results are expressed as the mean ± SD unless otherwise indicated. Student's paired or unpaired t tests, Wilcoxon tests, TABLE 1. Characteristics of the subjects (15 girls and 25 boys) at inclusion Median Chronological age (yr) Bone age (yr) Ht SDS for bone age SDS for chronological age Wt (% median for ht age) Ht velocity (cm/yr) Father's ht (cm) Mother's ht (cm)

Range

10.4 8.7

3.8-14.6 2.9-12.7

-1.2 -2.7 93.5 4.2 168.0 156.2

-4.0-+0.6 -4.5—2.1 76-116 1.6-5.7 153.0-180.0 143.5-171.3

SDS, SD score.

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GH THERAPY AND AUTOFEEDBACK IN NORMAL CHILDREN or x2 analysis were used as appropriate. Correlations between variables were calculated by linear regression analysis. P < 0.05 was considered significant.

Results During hGH therapy (0-12 months) Growth data Figure 1 shows the individual height velocities (centimeters per yr) before, during the 2 successive 6-month periods of hGH therapy, and during the 6 months of

treatment interruption. Overall, height velocity was 4.3 ± 0.9 before hGH treatment, 8.3 ±1.9 during the first 6 months, and 6.9 ± 1.6 during the second 6 months. There was no difference according to schedule of injections (morning to evening: 4.5 ± 0.7 before hGH therapy, 8.2 ± 2.3 and 7.3 ± 1.7 during the first and second 6 months, respectively; evening to morning: 4.2 ± 1.0 before hGH therapy, 8.4 ± 1 . 4 and 6.4 ± 1 . 4 during the first and second 6 months, respectively). The mean height velocity during the first 6 months was higher than that before treatment (P < 0.001). During the second 6 months, it

2

&

MORNING

EVENING

>

velocity (cm/

FIG. 1. Individual height velocities (centimeters per yr) before hGH therapy, during the first and the last 6 months of hGH therapy, and 6 months after discontinuation of hGH therapy. A, Height velocities for the subjects assigned to the morning to evening injection schedule (n = 19); B, height velocities for the subjects assigned to the evening to morning injection schedule (n = 19). Solid lines represent prepubertal subjects, and dashed lines subjects who entered puberty in the course of the study (stage 2 for genitalia or breast development).

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18 Time (Months) 15

NO hGH THERAPY

12

\ 9

z

/A

6

3

B 0

12

18

Time (Months)

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JCE&MM991 Vol73«No6

CHANOINE ET AL.

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was still higher than that before treatment (P < 0.001), but was significantly lower than that in the initial 6 months (P < 0.005). There was no difference in the growth responses of boys and girls. Neither pretreatment height velocity nor increase in height velocity under therapy were correlated with chronological or bone age. In contrast, absolute height velocity at the end of the 12 months of therapy was negatively correlated with chronological age (r = —0.42; P < 0.01) and bone age (r = —0.38; P < 0.05). There was a strong negative correlation between the pretreatment height velocity and the growth response (r = -0.72; P < 0.001). Weight was 95.0 ± 8.8% of median weight for height age before treatment and increased to 98.1 ± 9.0% after 12 months hGH therapy (P < 0.001). Eleven subjects (2 girls and 9 boys) entered puberty and reached Tanner stage 2 or 3 at 12 months. Deleting the data of these subjects did not modify the significance of the differences reported above. Thirtythree of 38 subjects (87%) who completed 12 months of therapy showed an increase in height velocity greater than 2 cm/yr. Two of the nonresponders developed antibodies (1 with high binding capacity), and the 3 others (2 prepubertal and 1 pubertal) had pretreatment height velocities that were equal to or higher than the group mean ± SD. Bone age increased by 1.1 ± 0.5 yr during the 12 months of treatment. Predicted adult height increased by 2.8 ± 1.8 cm (P < 0.001). IGF-I levels and GHRH tests (Table 2)

injection unknown (n = 3), GHRH not injected (n = 4), and positive antibodies resulting in markedly elevated baseline GH (n = 2). Baseline GH values were similar before and during hGH treatment and were not influenced by the time interval since the last hGH injection. There were significant 36% and 33% decreases in the maximum GH response and the GH secretory area, respectively, compared to the values measured before hGH therapy when the last hGH injection was performed 12 h before the test. When the last injection was performed 24 or 36 h before the test, no significant differences were observed. IGF-I values were similar at 12 and 24 h and significantly lower 36 h than 12 h after the last hGH injection (P < 0.01). Antibody formation

All subjects had a percent serum binding for labeled hGH similar to the control value in both assays before the beginning of therapy. During therapy, only one subject developed antibodies to hGH with a high binding capacity; he was detected in both laboratories (binding capacity, 4.57 ng/mL at Lilly and 4.71 ng/mL at Leuven), and his height velocity increased only from 4.8 to 5.7 cm/yr. Another subject was detected only at Lilly; he had a much lower binding capacity (0.08 /zg/mL), and his height velocity increased from 3.7 to 5.6 cm/yr. ECP antibodies remained negative throughout the study. Biological data

Although all IGF-I values were within the normal range for age before therapy, 37 of 38 (97%) values were below the median for age (15). Overall, IGF-I increased from 0.6 ± 0.3 U/mL before to 1.0 ± 0.5 U/mL after 12 months of therapy (P < 0.001). Most of the increase occurred during the first 6 months (mean ± SD IGF-I at 6 months, 0.9 ± 0.5 U/mL). The increase in IGF-I levels and the growth response were not correlated. The results of 69 pairs of GHRH tests were analyzed. The 11 missing pairs were due to children not completing 12 months of therapy (n = 2), time since last hGH

Blood chemistry and hematology panels and thyroid function tests were within the normal range for age before treatment and did not change significantly during the study. Testosterone in boys and estradiol in girls were within the prepubertal range before therapy and increased appropriately during puberty. After discontinuation of hGH therapy (12-18 months) Seven additional subjects (2 girls and 5 boys) entered Tanner stage 2 during the 6 months without hGH ther-

TABLE 2. Baseline GH, peak GH, and GH secretory area values during GHRH testing, and IGF-1 values before and during (at 6 or 12 months) hGH therapy (trt) as a function of the time interval since the last hGH injection 24 h post-hGH

12 h post-hGH Before trt Baseline GH ing/h) Maximum peak GH (/ig/L) GH secretory area (103 ^g/min-L) IGF-I (U/mL)

6.9 ± 52.8 ± 3.1 ± 0.6 ±

5.6 34.2 2.0 0.3

During trt 5.0 ± 34.5 ± 2.1 ± 1.1 ±

2.5 29.1" 1.4° 0.66

Before trt 6.6 ± 52.5 ± 3.0 ± 0.5 ±

5.7 35.5 2.0 0.3

36 h post-hGH

During trt 6.0 ± 48.5 ± 3.1 ± 1.0 ±

4.1 36.7 2.0 0.66

Before trt

During trt

6.8 ± 52.2 ± 2.9 ± 0.5 ±

6.6 ± 3.1 48.1 ± 41.1 2.7 ± 0.2 0.8 ± 0.4"

4.8 37.4 0.2 0.2

GHRH testing and IGF-I determinations were performed in the subjects 12 (n = 24), 24 (n = 24), and 36 (n = 21) h after the last hGH injection. Values are the mean ± SD. " P < 0.01 vs. before treatment. * P < 0.005 vs. before treatment.

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GH THERAPY AND AUTOFEEDBACK IN NORMAL CHILDREN

apy. Overall, in the 36 subjects who completed the 18month study, height velocity was 3.9 ± 1.5 cm/yr, significantly lower (P < 0.001) than that during each of the 6month periods of treatment, but not significantly different from that before treatment. Persistent acceleration was only observed in the 4 subjects who had entered puberty during the first 6 months of the study. Conversely, catch-down growth was observed more frequently in prepubertal subjects [13 of 20 prepubertal (65%) vs. 3 of 16 (19%) pubertal; P < 0.02]. Weight for height values remained similar to those at 12 months in prepubertal as well as pubertal subjects. The mean IGFI level at 18 months was 1.2 ± 0.8 U/mL for the whole group; in prepubertal subjects, mean IGF-I values were lower at 18 months (0.6 ± 0.3 U/mL) than at 12 months (0.8 ± 0.3 U/mL; n = 20; P < 0.01), while they were higher in pubertal subjects (1.9 ± 0.8 compared to 1.3 ± 0.6 U/mL; n = 1 6; P < 0.025). The 2 subjects who developed hGH antibodies returned to specific binding capacities below the detection limit (0.02 /ig/mL) after 6 months without hGH therapy.

Discussion Several short term studies recently demonstrated that hGH therapy at doses of 0.3 IU (0.1 3 mg) to 0.7 IU (0.29 mg)/kg-week for 6-12 months resulted in an increase in growth velocity in 43-86% of short, slowly growing children without GH deficiency (see review in Refs. 6 and 17). The present work shows that the injection of hGH at a dose of 18 IU (7.5 mg)/m2-week [corresponding to ~0.6 IU (0.25 mg)/kg- week] for 1 yr results in an increase in height velocity greater than 2 cm/yr in 87% of the subjects. The strong negative correlation between the increase in height velocity during therapy and pretreatment height velocity has been noted previously (18). This negative correlation could be in part artifactual, due to the known oscillatory nature of growth in some normal children (7). Alternatively, it is possible that children with the slowest height velocity are, through unknown mechanisms, the most sensitive to the growth-promoting effects of hGH. GH therapy also induced a small but significant increase in weight for height, possibly reflecting the increased appetite reported by most parents. Although the hGH dose used in this study was greater than the secretion rate of hGH in normal prepubertal children (19), it did not result in supraphysiological IGFI values. In the present study we postulated that evening hGH injections in non-GH-deficient subjects could induce a negative feedback on the nocturnal endogenous GH surge, and that the time of injection could, therefore, influence the growth response. Yet, we found no significant difference in growth velocity between the patients

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receiving hGH injections in the morning and those receiving them in the evening. This finding is similar to that of Matustik et al. (5) in children with GH deficiency and suggests that the greater bioavailability of evening hGH injections reported by Jorgensen et al. (4) does not influence the growth response. To assess tKe effect of hGH treatment on pituitary GH reserve, we performed GHRH tests at various times after the last hGH injection. The GH secretory area as well as the peak GH response to GHRH were decreased by only one third 12 h after the last injection. This effect was no longer present 24 or 36 h after the last injection. In contrast, Ross et al. (20) found a 75% decrease in the GH response to GHRH in adults 12 h after a single sc dose of 8 IU (3.3 mg) methionyl-GH and a 60% decrease 24 h after the sc injection of 4 IU (1.7 mg) methionylGH twice a day for 3 consecutive days. In the only other studies of GH autofeedback in children, Nakamoto et al. (21) noted only a 40% decrease in the GH response to GHRH 16-20 h after a hGH injection of 0.1 IU (0.04 mg)/kg, and Wu et al. (22) reported unchanged spontaneous GH secretion 48 h after the last injection in prepubertal children treated for 1 yr with three injections per week. On the other hand, Ghigo et al. (23) showed that the GH response to the second of two GHRH boluses given 2 h apart is blunted in adults, but not in children. Taken together, these data suggest that children are less sensitive to GH autofeedback than adults. The fact that the GH response to GHRH is decreased at 12, but not 24, h, while IGF-I values are similar at both time points, is consistent with the observations of Rosenthal et al. (24) and Ross et al. (20) that the impaired GH response to GHRH after exogenous hGH treatment is mediated not by circulating IGF-I but, more likely, by GH itself. Height velocity was greater during the first 6 months than during the second 6 months of treatment. The waning effect occurred even though the dose of hGH was adjusted to body surface area after 6 months. Wit et al. (25) showed that doubling the dose from 14 to 28 IU (5.8 to 11.6 mg)/m2 • week during the second year of treatment overcame the waning effect, but the effect of such regimen on final height prediction was unclear. The significance of the increase of 2.8 cm in the predicted adult height that we observed after 1 yr of therapy should, therefore, be considered with great caution. After discontinuation of treatment, height velocity returned to pretreatment values or less in all prepubertal patients. This suggests that the growth acceleration was indeed due to hGH. There were no clinical or biological side-effects of therapy, except for the development of antibodies to hGH, with a measurable capacity in two subjects. This 5% incidence is in the same range as that reported by others for pituitary hGH (26). The causal relationship

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between the presence of high serum hGH-binding capacity and an increase in growth velocity less than 2 cm/yr during hGH therapy is difficult to evaluate. It has been estimated that growth attenuation was likely when the measured capacity was above 1 ^g/L (27), which was the case for only one subject in the present study. Except for hGH antibodies, the reason why some subjects do not respond to hGH treatment is unclear. High pretreatment height velocity has been associated with a lower response to hGH therapy in some studies (18), but not in others (28). We found that the nonresponder subjects with negative antibodies had pretreatment height velocities equal to or greater than the group mean -I- 1 SD. We conclude that hGH therapy increases height velocity in short, slowly growing normal children independently of the time of hGH injection. However, the growth response is heterogenous, and the acceleration induced is modest and wanes after 6 months. This waning effect occurs in spite of the fact that IGF-I levels remain stable, and endogenous GH secretion is only weakly and transiently inhibited, suggesting that it is the growth plate itself that becomes relatively refractory to hGH and/or IGF-I over time (29). Likewise, the catch-down phenomenon after hGH is discontinued is unlikely to be related to a persistent diminution of pituitary responsiveness. Finally, this therapy, at the dose studied, is well tolerated, does not induce supraphysiological IGF-I levels, and does not accelerate bone maturation. Long term controlled studies will be needed to determine whether this therapy increases adult height. Acknowledgments We are indebted to the other members of the Belgian Study Group for Pediatric Endocrinology for providing patients and for helpful discussions: Jean-Pierre Bourguignon, Jean De Schepper, Francis de Zegher, Marc Du Caju, Lutgarde Dooms, Christian Ernould, Claudine Heinrichs, Karl Logghe, Paul Malvaux, Guy Massa, and Marc Vandeweghe. We thank Prof. R. Bouillon for the determination of antibodies to hGH, and G. Art for technical assistance. We also wish to thank Drs. J.-C. Reiter and H. Schmitt for their help in the organization of the study. hGH (Humatrope) was kindly provided by Eli Lilly Benelux.

References 1. Underwood LE, Rieser PA. Is it ethical to treat healthy short children with growth hormone? Acta Paediatr Scand. 1989;(Suppl 362):18-23. 2. Finkelstein JW, Roffwarg HP, Boyar RM, Kream J, Hellman L. Age-related change in the twenty-four-hour spontaneous secretion of growth hormone. J Clin Endocrinol Metab. 1972;35:665-70. 3. Rose SR, Ross JL, Uriarte M, Barnes KM, Cassorla FG, Cutler GB. The advantage of measuring stimulated as compared with spontaneous growth hormone levels in the diagnosis of growth hormone deficiency. N Engl J Med. 1988;319:201-7. 4. Jorgensen JOL, Moller N, Lauritzen T, Alberti KGMM, Orskov H, Christiansen JS. Evening versus morning injections of growth

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hormone (GH) in GH deficient patients: effects on 24 h patterns of circulating hormones and metabolites. J Clin Endocrinol Metab. 1990;70:207-14. 5. Matustik MC, Furnaletto RW, Meyer WJ. Chronobiologic considerations in human growth hormone therapy. J Pediatr. 1983; 103:543-6. 6. Van Vliet G. Use of growth hormone in the management of growth disorders. In: Sizonenko PC, Aubert ML, eds. Developmental Endocrinology. Serono Symp. New York: Raven Press; 1990:195-202. 7. Marshall WA. Evaluation of growth rate in height over periods of less than one year. Arch Dis Child. 1971;46:414-2O. 8. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child. 1976;51:170-9. 9. Tanner JM. Growth at adolescence. Oxford: Blackwell; 1962. 10. Vanderschueren-Lodeweyckx M, Wolter R, Malvaux P, Eggermont E, Eeckels R. The glucagon stimulation test: effect on plasma GH and on immunoreactive insulin, cortisol, and glucagon in children. J Pediatr. 1974;74:182-7. 11. Tanner JM, Whitehouse RH, Takaishi M. Standards from birth to maturity for height, weight, height velocity, and weight velocity: British children. Arch Dis Child. 1966;41:454-71. 12. Tanner JM, Whitehouse RH, Marshall WA, Healy MJR, Goldstein H. Assessment of skeletal maturity and prediction of adult height, 2nd ed. London, New York: Academic Press; 1983. 13. Tanner JM, Landt KW, Cameron N, Carter BS, Patel J. Prediction of adult height from height and bone age in childhood. Arch Dis Child. 1983;58:767-76. 14. Van Vliet G, Bosson D, Robyn C, et al. Effect of growth hormonereleasing factor on plasma growth hormone, prolactin, and somatomedin-C in hypopituitary and normal short children. Horm Res. 1985;22:32-45. 15. Van Vliet G, Bosson D, Rummens E, Robyn C, Wolter R. Evidence against growth hormone-releasing factor deficiency in children with idiopathic obesity. Acta Endocrinol (Copenh). 1986;279(Suppl):403-10. 16. Sportsman JR, Smith WC, Winely CL. Practical automation and interpretation of quantitative assays of antibodies to therapeutic proteins, illustrated with human growth hormone. Clin Chem. 1989;35:1623-30. 17. Van Vliet G. Growth hormone treatment of children with non growth hormone deficient short stature. In: Imura H, Shizume K, Yoshida S, eds. Progress in endocrinology 1988. Excerpt Med Int Congr Ser 799. Amsterdam: Elsevier; 1988;825-7. 18. Van Vliet G, Styne DM, Kaplan SM, Grumbach MM. Growth hormone treatment for short stature. N Engl J Med. 1983;309:1016-22. 19. Albertsson-Wikland K, Rossberg S, Libre E, Lundberg LO, Groth T. Growth hormone secretory rates in children as estimated by deconvolution analysis of 24 h plasma concentration profiles. Am J Physiol. 1989;257:E809-14. 20. Ross RJM, Borges F, Grossman A et al. Growth hormone pretreatment in man blocks the response to growth hormone-releasing hormone; evidence for a direct effect of growth hormone. Clin Endocrinol (Oxf). 1987;26:117-23. 21. Nakamoto JM, Gertner JM, Press CM, Hintz RL, Rosenfeld RG, Genel M. Suppression of the growth hormone (GH) response to clonidine and GH-releasing hormone by exogenous GH. J Clin Endocrinol Metab. 1986;62:822-6. 22. Wu RHK, Louis YST, DiMartino-Nardi J, et al. Preservation of physiological growth hormone (GH) secretion in idiopathic short stature after recombinant GH therapy. J Clin Endocrinol Metab. 1990;70:1612-5. 23. Ghigo E, Goffi S, Mazza E, et al. Repeated GH-releasing hormone administration unravels different GH secretory patterns in normal adults and children. Acta Endocrinol (Copenh). 1989;120:598-601. 24. Rosenthal SM, Kaplan SL, Grumbach MM. Short term intravenous infusion of growth hormone (GH) inhibits GH-releasing hormone-induced GH secretion: a time-dependent effect. J Clin Endocrinol Metab. 1989;68:1101-5. 25. Wit JM, Fokker MH, de Muinck Keizer-Schrama SMPF, et al. Effects of two-years of methionyl growth hormone therapy in two

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GH THERAPY AND AUTOFEEDBACK IN NORMAL CHILDREN dosage regimens in prepubertal children with short stature, subnormal growth rate, and normal growth hormone response to secretagogues. J Pediatr. 1989;115:720-5. 26. Buzi F, Buchanan CR, Morrell DJ, Preece M. Antigenicity and efficacy of authentic sequence recombinant growth hormone (Somatropin): first-year experience in the United Kingdom. Clin Endocrinol (Oxf). 1989;30:531-8. 27. Kaplan SL, Savage DCL, Suter S, Wolter R, Grumbach MM. Antibodies to human growth hormone arising in patients treated

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with human growth hormone: incidence, characteristics, and effects on growth. In: Raiti S, ed. Advances in human growth hormone research, publication no. NIH 74-612. Washington DC: DHEW; 1974;725-47. 28. Genetech Collaborative Study Group. Idiopathic short stature: results of a one-year controlled study of human growth hormone treatment. J Pediatr. 1989;115:713-9. 29. Mosier HD, Dearden LC, Jansons RA, Hill RR. Cartilage sulfatation during catch-up growth after fasting in rats. Endocrinology. 1978;102:386-92.

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Growth hormone (GH) treatment in short normal children: absence of influence of time of injection and resistance to GH autofeedback.

Forty prepubertal subjects (25 boys and 15 girls) with idiopathic short stature, aged 3.8-14.6 yr, were randomly allocated to receive sc injections of...
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