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Christie Hospital (S.M.S.), Manchester M20 4BX, United Kingdom; PSI (E.S.), St. Petersburg 19119, Russia; Eli Lilly & Co. (M.C., J.J.C.), Indianapolis, Indiana 46285; Children’s Hospital (M.P.), 04011 Kosice, Slovakia; Department of Pediatrics, Third Faculty of Medicine, Charles University (J.L.), CZ-10081 Prague, Czech Republic; Lilly Research (C.J.C.), Windlesham GU20 6PH, United Kingdom; Lilly Research (W.F.B.), Bad Homburg D-61350, Germany; and Lilly Research (A.F.A.), 50019 Sesto Fiorentino, Italy
Address all correspondence and requests for reprints to: Dr. Stephen M. Shalet, Department of Endocrinology, Christie Hospital, National Health Service Trust, Wilmslow Road, Manchester, United Kingdom M20 4BX. E-mail: stephen.m.shalet{at}man.ac.uk.
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Abstract |
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Introduction |
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One reason for this discrepancy may be the current practice of stopping pediatric GH replacement at final height. Maturation of body mass components is not fully completed at final height, and in healthy subjects bone mass accumulation continues until peak bone mass is attained (4). In addition, the ratio of LBM/height increases, particularly in males, until 20 yr and beyond (5, 6), and changes in fat distribution, even if less pronounced than during the period of rapid longitudinal growth, continue into adulthood (7).
After discontinuation of pediatric GH treatment, progression to peak bone mass is attenuated, and a significant decrease is seen in LBM, paralleled by an increase in FM, in CO GHD patients (8, 9, 10, 11). Accordingly, continued GH action beyond final height is critical to complete maturation of body mass components in CO GHD subjects. Indeed, in a controlled study in CO patients with severe GHD, we have recently shown that bone turnover significantly accelerates, and up to 10% of bone mass is accumulated within 2 yr of GH reinstitution (12). We now report the GH-induced changes in LBM, FM, IGF-I/IGF-binding protein-3 (IGFBP-3), and lipid status seen in the same cohort of patients during the 2 yr of GH reinstitution.
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Subjects and Methods |
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Details of the study protocol have been previously reported (12); all patients gave informed consent, and the study was performed with appropriate ethical approval and according to the Declaration of Helsinki and good clinical practice guidelines. In brief, a total of 149 subjects from 11 countries who had finished pediatric GH treatment, had a height velocity of less than 1 cm/yr, and had the diagnosis of GHD reconfirmed by a peak serum GH level below 5 µg/liter in response to a stimulation test (insulin, arginine, glucagon, or arginine/L-dopa) as well as a serum IGF-I concentration below the first percentile for age and gender were randomized to one of three treatment groups: group 1 (n = 59) received GH (Humatrope, Eli Lilly & Co., Indianapolis, IN) at 25.0 µg/kg·d (0.18 mg/kg·wk; pediatric dose); group 2 (n = 58) received GH at 12.5 µg/kg·d (0.09 mg/kg·wk; adult dose); and group 3 (n = 32) patients did not receive any GH (control). Before entering the study, patients had to be on stable hormone replacement for additional pituitary hormone deficits. In females, estrogen replacement was provided by oral estrogens in all but one subject who was receiving transdermal estrogen; overall, more than 60% of the females received estrogen replacement.
LBM and FM were assessed by dual energy x-ray absorptiometry (DXA) at baseline, 12 months and 24 months. Serum samples were taken for determination of total, low-density (LDL) and high-density lipoprotein (HDL) cholesterol, IGF-I, and IGFBP-3 concentrations at baseline and every 6 months during the study.
Laboratory methods
DXA machines were all calibrated with the same phantom, and DXA data were transferred electronically for all readings to be performed centrally (Synarc, Inc., Portland, OR). All IGF-I and IGFBP-3 determinations were performed at a central laboratory (University Children’s Hospital, Giessen, Germany). Total cholesterol, HDL cholesterol, and triglycerides were measured centrally (Covance Central Laboratory Services, Indianapolis, IN), with LDL cholesterol determined by the Friedewald calculation.
Data analysis
Height SD scores at baseline were calculated by reference to an age- and sex-matched healthy population (13). The protocol was not completed by 26 patients, mainly due to patient decision, with only two patients discontinued due to unrelated adverse events. The primary analysis used the intent-to-treat population, and all other analyses used the per-protocol population. For all variables, within-group changes from baseline were analyzed by paired t tests or signed rank tests, depending on the normality of the data. Differences among treatment groups were analyzed using an analysis of covariance model, adjusting for height (3) and incorporating effects for treatment, country, and treatment by country interactions. A similar analysis using height at the end of 2 yr of treatment had minimal difference in the results and did not change significances or conclusions; therefore, only the analysis adjusting for baseline height is presented. This was followed by pairwise comparisons using least squares means to examine treatment effects as differences between all GH-treated patients and controls as well as differences between the two GH doses.
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Results |
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The baseline demographic, anthropometric, and diagnostic data of the enrolled patients are presented in Table 1
by randomization group. Groups were well balanced with respect to gender, age, height, body mass index (BMI), time since diagnosis of GHD, time since last GH injection, and GHD diagnostic criteria.
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Baseline serum IGF-I and IGFBP-3 (Table 1
) concentrations were very low, and neither SD scores nor actual concentrations differed among the three groups. Baseline values as well as treatment changes in LBM and FM are shown in Table 2. In the control group, small, but statistically nonsignificant, increases in both LBM and FM were seen over the 2-yr study period. In contrast, the increase in LBM in the two treatment arms was highly significant (P < 0.001 for treatment effect vs. control) at both the 1- and 2- yr end points. However, the 0- to 2-yr change with the higher pediatric dose (5.2 ± 4.4 kg) was not statistically different from the 0- to 2-yr change seen with the lower adult dose (5.1 ± 3.9 kg; P = 0.447). In parallel, FM decreased at the 2-yr end point with a significant GH treatment effect vs. control (P = 0.029), but, similar to LBM, without a dose effect (change with adult dose, –1.6 ± 5.8 kg; change with pediatric dose, –1.1 ± 4.0 kg; P = 0.779).
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. In the control group serum total cholesterol concentrations as well as the LDL/HDL ratio significantly increased from baseline to the 2-yr end point (P = 0.009 and P = 0.039, respectively). In the two treatment arms, within-group changes in serum total cholesterol were not significant, and there was no treatment effect. For the LDL/HDL ratio, the within-group decrease was significant (P = 0.016) only for the higher dose after 1 yr; however, the treatment effect vs. the untreated control was very significant (P < 0.001) at 1 yr and was still significant after 2 yr (P = 0.050).
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For all patients, baseline IGF-I concentrations as well as IGF-I SD scores were significantly higher in males than in females [IGF-I, 78.0 ± 51.5 vs. 58.4 ± 47.4 µg/liter (P = 0.011); IGF-I SD score, –6.3 ± 2.9 vs. –8.1 ± 2.8 (P < 0.001)]. Over the 2-yr study period, the GH treatment effect on IGF-I levels was dose-dependent in females, but not so in males, as shown in Fig. 1. At the 2-yr end point, IGF-I values in females, although significantly (P < 0.001) higher than those in the controls, were still more than 4 SD lower than normal with the lower GH dose (–4.9 ± 2.4) and were in the normal range with the higher dose (–0.87 ± 2.5; P = 0.008). In males, the average IGF-I SD scores at the 2-yr end point were in the normal range with both GH dosages, and although the SD score in the pediatric dose group was higher than that in the adult dose group, the difference was not statistically significant (–1.40 ± 1.20 and –1.86 ± 3.03; P = 0.790).
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. In males there was no difference between the two doses for LBM and FM changes at either the 1- or 2-yr end point. In contrast, changes in females appeared to be dose dependent, but the difference between the two doses reached statistical significance only at 1 yr. With both doses in females, most of the effect on FM seen during the first year was lost by the 2-yr end point. For both sexes, persistent changes in body composition, specifically in LBM, were significant and more pronounced in males than in females. Therefore, because the small, but significant, increase in height indicated that patients were still developing, we examined the relationship between LBM and height change. In Fig. 2 the 0- to 2-yr change in the LBM/height ratio is shown by dose and gender. Although there was no gender difference in the control group, the change was significantly greater in males than in females for both adult (P < 0.001) and pediatric (P = 0.031) dose groups.
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Discussion |
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2.5 cm), is minor, but suggests that when GH treatment was stopped, some growth potential remained. During the 2 yr of the study, tracking to final height continued and accounted for a gain of 0.05 SD, about 0.3 cm, in the control group and 0.15 SD, about 1 cm, in the two treatment groups. The GH-induced increases were statistically significant, but minor in terms of longitudinal, one-dimensional growth. However, they are a sensitive indicator that the overall growth process, or total somatic body maturation, was not fully completed and was still GH responsive. The progress to peak bone mass shown previously (12) indicates that patients given additional GH treatment track their individual bone mass target, and this principle should hold for other body components.
Two other studies to date using DXA assessment have examined body composition changes with GH replacement in young CO adult cohorts. One, by Vahl et al. (14), studied the 1-yr effect of 2.0 IU/m2·d (6.0 µg/kg·d) in 10 subjects who had discontinued pediatric GH treatment at final height 1 yr earlier and found quantitative changes in LBM and FM comparable to those seen in our study. The second study, published very recently (15), had the same design and dose regimen as ours and randomized 64 patients to a 2-yr treatment with either placebo or GH (12.5 or 25.0 µg/kg·d). According to the study criteria, however, patients up to 35 yr of age could be enrolled, resulting in a mean age of 23.8 yr, i.e. 3–5 yr older than our patients. In this cohort, unlike the cohort of the present study, the LBM and FM changes from baseline to the 2-yr end point exhibited a significant dose dependency. However, the magnitude of the overall LBM increase (3.5% with the low dose and 6.5% with the high dose) was significantly less than the 13–14% seen in the present study and that by Vahl et al. (14). In contrast, the FM changes seen with the higher dose of 25.0 µg/kg·d, approximately –7% (15), were comparable with those seen in our study with both dosages. Thus, there are discrepancies between studies in the age and dose dependency of the body composition response to GH. It is likely that size and baseline status of the study subjects account to a large extent for these discrepancies, but maturational stage seems to be an important factor. In fact, in the study by Underwood et al. (15), a larger proportion of patients were older than those in the present study and that by Vahl et al. (14) and as such were no longer in transition, but already at adult age. This difference may explain their overall smaller LBM change, which is quantitatively comparable to that seen in AO adult GHD subjects who, over a comparable period, usually gain not more than 5–6% LBM (16, 17, 18). Thus, the GH response during transition is still of the pubertal type, and it should be noted that the enhanced LBM increase experienced by our patients regains 70–85% of the baseline deficit we have previously described (3). The apparent age dependency of the skeletal and body composition responses to 2 yr of GH replacement implies that there is a critical window of therapeutic opportunity for optimizing these parameters, with theoretical health benefits of reduced fracture risk later in adult life and improved exercise capacity and muscle strength throughout adult life. These potential gains are likely to be attenuated if GH replacement is delayed for too long a period of time.
Neither of the two previously reported studies analyzed the data by gender; as shown in the present report, the nature of the body composition changes occurring during the transition period can best be appreciated when not just age and dose, but also gender, differences are taken into account. The opposite changes in LBM and FM were highly significant and dose independent in males, but were less pronounced in females, in whom the effect on FM, although significant and dose dependent during the first year of GH treatment, tended to disappear by the 2-yr end point with both dosages. In light of our data, it is likely that the dose dependency found by Underwood et al. (15), specifically in the FM response, reflects the composite response in males and females. In normally growing children, the relationship between LBM and height is exponential, with the LBM/height ratio increasing in males well beyond age 20 yr and in females until age 14 yr, with no significant increases thereafter (5, 6). In addition, during normal development from early adolescence until adulthood, males lose up to 8% FM and females gain up to 6% FM (7). Therefore, the different changes seen in the LBM/height ratio and the contrasting changes in FM seen in males and females suggest that the pattern of response to GH replacement in our patients primarily reflects developmental gender dimorphism. It would appear that resumption of GH replacement not only optimizes progress to peak bone mass, but also affects the late stage of gender-specific maturation to adult body composition. This gain is quantitatively small for height, i.e. for one-dimensional growth, but is clinically very significant for components of body mass, i.e. for three-dimensional growth.
Baseline as well as GH-stimulated IGF-I levels in our patients were, on the average, lower than those in other studies of CO subjects after discontinuation of pediatric GH treatment (9, 11, 14, 16). Direct comparison is difficult because GH dosage, age at onset of GHD, time since last pediatric GH injection, and severity of GHD all affect IGF-I levels (19, 20, 21). However, the finding that adult CO patients have lower IGF-I concentrations than AO patients has been confirmed in multiple studies (15, 18, 19, 20, 21, 22). Previously we (3, 12) and others (20, 22) have speculated that the IGF-I levels seen in CO adult patients are an expression of total exposure to GH (endogenous as well as exogenous) over time during prepubertal and pubertal development. In the present study IGF-I SD scores in females remained pathologically low with the lower GH dose (–4.9 SD) and were in the normal range (–0.87 SD) with the higher dose, whereas in males, average values were essentially normal with both doses, and the dose effect over time was not statistically significant. Thus, the IGF-I data confirm the gender dimorphism seen in the LBM and FM responses and would suggest that for the transition period a higher GH replacement dose is necessary in females than in males. It is, however, unclear from our data to what extent the male/female difference in baseline as well as stimulated IGF-I levels is a true gender difference or is due to other factors, such as gonadal replacement and, specifically, estrogen treatment (22, 23, 24). Oral estrogen use was, in fact, widespread in our patients, and we agree with Underwood et al. (15) that more studies are required to clarify this aspect.
Baseline serum total cholesterol and the LDL/HDL ratio did not differ among the three treatment arms. During the study there were significant increases in the control group and no significant changes in the GH-treated patients. The findings in the control group are consistent with those reported in other studies (11), showing a deterioration of lipid status after withdrawal of pediatric GH treatment. Restoration of GH replacement prevents this deterioration, with the higher dose showing a statistically nonsignificant trend to decrease values from baseline. However, as the mean baseline serum total cholesterol levels were in the normal range, the main treatment effect, achieved with the lower dose, was to maintain levels within the normal range.
In summary, we have shown that important maturational, GH-dependent events take place in GHD patients during the transition period into adulthood. This relates not only to the established achievement of peak bone mass, as we have previously shown (12), but also to other body components. Thus, the transition period finalizes the three-dimensional somatic development, and GHD subjects require continued adequate GH replacement into adulthood. In the absence of GH replacement, the gain in LBM is severely attenuated, reducing potential exercise capacity and muscular strength in adult life. Furthermore, during this maturational period there is a critical window of opportunity for GH replacement to optimize acquisition of LBM. The pattern of GH-induced changes in body composition maintains the gender dimorphism characteristic of normal pubertal development. The GH dose response seen in transition patients indicates that in males, a normal adult dose is adequate, whereas females may require a dose still in the pediatric range. Our data, however, cannot answer the question of whether this difference is due to a true male/female difference in sensitivity to GH action or to exogenous factors, such as administration of oral estrogen.
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Acknowledgments |
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Footnotes |
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Abbreviations: AO, Adult onset; BMC, bone mineral content; CO, childhood onset; DXA, dual energy x-ray absorptiometry; FM, fat mass; GHD, GH deficient, GH deficiency; HDL, high-density lipoprotein; IGFBP-3, IGF-binding protein-3; LBM, lean body mass; LDL, low-density lipoprotein.
Received March 22, 2004.
Accepted June 24, 2004.
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) and male (
) CO GHD patients.