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Eli Lilly \|[amp ]\| Co. (A.F.A.), Florence 50019, Italy; Christie Hospital (S.H., S.M.S.), Manchester M20 4BX, United Kingdom; Lilly Research Centre (P.C.B., P.F.), Windlesham, Surrey GU20 6PH, United Kingdom; Eli Lilly \|[amp ]\| Co. (J.C.), Indianapolis, Indiana 46285; and Eli Lilly \|[amp ]\| Co. (W.F.B.), 61350 Bad Homburg, Germany
Address all correspondence and requests for reprints to: Dr. Stephen M. Shalet, Department of Endocrinology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom. E-mail: . Stephen.M.Shalet{at}man.ac.uk
Abstract
If GH therapy of children with GH deficiency (GHD) has been adequate, body composition should be comparable to that of patients who have undergone normal childhood development and become hypopituitary thereafter. To assess this, body composition was determined in 92 patients with childhood onset (CO) GHD, aged 18–30 yr, who had been treated to final height with GH for 8.98 ± 4.30 yr and had stopped treatment 1.57 ± 1.20 yr previously, but who remained GHD (assessed by a GH stimulation test and IGF-I values). These were compared with 35 age-matched GH-naïve hypopituitary patients with adult onset (AO) GHD. Lean body mass, fat mass, and total bone mineral content were assessed by dual energy x-ray absorptiometry and corrected for actual height. CO patients were shorter (CO height, -1.18 ± 1.16 SD score; AO height, -0.38 ± 1.12 SD score; P < 0.001) and had lower body mass index (CO, 23.19 ± 5.76 kg/m2; AO, 28.9 ± 6.27 kg/m2; P < 0.001) than the AO group. Although there were gender differences, within genders CO patients had lower lean body mass, fat mass, and bone mineral content (P < 0.001 in all cases) compared with AO patients. Standard deviation scores for IGF-I (CO female, -9.2 ± 3.1; AO female, -5.2 ± 2.6; CO male, -6.4 ± 2.7; AO male, -3.5 ± 2.3; P < 0.001 within each gender) and IGFBP-3 (CO female, -3.5 ± 2.5; AO female, -1.7 ± 1.5; CO male, -2.8 ± 2.0; AO male, -1.1 ± 1.6; P < 0.001 within each gender) were significantly lower in the CO group. These results suggest that patients with CO GHD who were treated to final height suffer a significant maturational deficit despite GH replacement during childhood.
CONVENTIONAL THERAPY WITH recombinant human GH in children with GH deficiency (GHD) is stopped when epiphyseal closure has been attained (i.e. at final height). This reflects the focus on height as a measure of the success of replacement GH therapy. However, experience gained from GH replacement therapy in adults with GHD has documented the importance of GH action for the development and maintenance of a normal adult body composition and metabolic balance (1, 2, 3, 4). Childhood onset (CO) GHD patients discontinuing pediatric GH treatment after final height develop changes in body composition characteristic of adult GHD (5, 6, 7). The overall clinical presentation of young adults with CO GHD differs from that of adult onset (AO) GHD patients because they are, on average, smaller and have less muscle and bone mass and lower IGF-I and IGFBP-3 serum concentrations than AO patients (4, 8). However, the CO populations studied are generally much younger than the AO populations, and it is difficult to allow for age-related changes.
We have postulated that the heterogeneity between the two adult GHD entities is primarily due to a somatic immaturity of CO patients and that these patients, when compared with AO patients, suffer from a disease with two components: the developmental one, existing since childhood, and the metabolic one, with adult onset (8). Given the impact of any chronic disease of childhood on adult life, the definition of the developmental component is of relevance for 1) evaluation of the efficacy of pediatric GH therapy, and 2) assessment of adult long-term morbidity or mortality.
The aim of the present study was to evaluate somatic maturation after completion of pediatric GH treatment. Body composition and IGF-I/IGFB-3 status of adult CO hypopituitary patients with severe GHD who had been treated with GH during childhood were compared with that of GH-naïve subjects of comparable developmental age. Because AO subjects manifest the features of GHD only after normal pubertal growth and development, they provide the most suitable comparison for evaluation of the magnitude of the developmental component.
Patients and Methods
Patients
This study compared 92 CO GHD patients with 35 AO GHD patients, chosen with an age range of 18–30 yr to cover the time interval from postpuberty to attainment of peak bone mass. Patient characteristics for the two groups are shown in Table 1
. The CO patients were Caucasian subjects participating in a multinational, multicenter trial that was recruiting patients for study of effects of postpubertal GH intervention. They had a history of severe GHD, either idiopathic or organic, isolated or with multiple pituitary hormone deficiencies. Diagnosis of GHD had occurred before the onset of, or during, puberty, and all had received GH treatment during childhood until final height. Treatment duration had been 8.98 ± 4.30 yr, and the time since GH discontinuation was 1.57 ± 1.20 yr (range, 6 months to 5 yr). Data of GH-naïve, age-matched Caucasian AO patients were taken from the baseline visit of another large controlled multinational, multicenter GH efficacy trial carried out in adult hypopituitary GHD subjects. For the purpose of the present analysis, AO patients were defined as those in whom the diagnosis of GHD/hypopituitarism had been established after final height had been attained and who had a GH peak of less than 3 µg/liter to a standard insulin tolerance test [n = 28 (80%)] or alternative stimulation test [n = 7 (20%)]. The two multicenter clinical trials were carried out according to the guidelines of Good Clinical Practice and with approval from the Ethical Review Boards appropriate for each of the study centers.
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Serum IGF-I and IGFBP-3 levels were measured at a single central laboratory, using an IGFBP-blocked RIA with a large excess of IGF-II for determination of IGF-I and a specific RIA for IGFBP-3 (9).
Lean body mass (LBM), fat mass (FM), and total bone mineral content (BMC) were assessed by dual-energy x-ray absorptiometry (DEXA). DEXA machines were calibrated with the same phantom, and all DEXA readings were performed centrally. DEXA was performed in 25 of the AO patients (10 females and 15 males) and in 80 of the CO patients (20 females and 60 males).
Statistics
IGF-I and IGFBP-3 SD scores were calculated by comparison with gender- and age-matched reference standards after logarithmic transformation of the actual value (10). All DEXA values were normalized for actual height using the formula: (actual DEXA value/actual height) x 1.70 (11). Differences between the two patient groups were determined from two-tailed t tests, with a P value less than 0.05 considered to be significant. Target height was evaluated from the mean height of the two parents of the patient plus 6.5 cm for male patients or minus 6.5 cm for female patients. HeightSD score was calculated from actual height by reference to a normal population, and the difference between actual heightSD score and target heightSD score was examined in relation to the body composition measurements, with significance examined using Spearman rank correlations.
Results
The two patient groups were comparable with respect to age range, male/female balance, and peak GH values in responses to GH stimulation tests. As expected, a higher proportion of patients with CO GHD had a diagnosis of idiopathic GHD. Only two AO patients (5.7%) had isolated GHD, and more CO patients had isolated GHD compared with adult patients. CO patients were significantly shorter than AO patients. Their height SD score was -1.18 ± 1.16 (range, -4.2 to +1.7) compared with -0.38 ± 1.12 (range, -2.0 to +2.2) in the AO group (P < 0.001). The CO patients also weighed significantly less, with a body mass index (BMI) of 23.19 ± 5.76 kg/m2 compared with 28.9 ± 6.27 kg/m2 in the AO group (P < 0.001). On the other hand, as shown in Fig. 1, the distribution of BMI values in CO patients was similar to the distribution of values in AO patients (CO, 14.3–49.2 kg/m2; AO, 18.0–44.8 kg/m2).
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. For both measurements, CO patients had significantly (P < 0.001) lower values for LBM, FM, and BMC than AO patients. When the actual heightSD score minus target heightSD score was taken as an outcome measure of pediatric GH treatment in CO subjects, statistically significant correlations were found with LBM and BMC, but there was little correlation with FM (Table 3).
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. In both females and males, serum IGF-I and IGFBP-3 concentrations and SD score values were significantly (P < 0.001 in each case) lower in CO than in AO patients. Finally, when correlations of IGF-I and IGFBP-3 concentrations with height and body composition measures were examined, significant relationships were found with actual height and LBM in both GHD groups, and with BMC in CO but not AO patients (Table 5).
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GH peak values in stimulation tests and actual IGF-I/IGFBP-3 levels established the diagnosis of adult GHD in all patients included in this study. Specifically, in the CO subjects, a diagnosis of severe GHD was reconfirmed, thus making them a suitable group to assess outcome of pediatric treatment. All subjects had been treated in centers of excellence and had received state-of-the-art GH therapy, so their data provide an objective estimate of treatment outcome. The CO patients were significantly shorter than AO patients, with height being on average 97% that of the AO patients. Their mean final height SD score value of -1.18 ± 1.16 is in agreement with published literature (12, 13). Nevertheless, a large proportion of subjects had not reached their full growth potential, and about 40% of both females and males had a final height below the normal range. Another anthropometric measure, BMI, was significantly lower in CO than in AO, indicating that on the average CO patients had less body mass per unit height than AO patients. A height-normalized comparison of the individual components of body mass assessed by DEXA showed that CO patients had significantly less LBM, FM, and BMC than AO patients, thus confirming previous findings in nonage-matched patients (4, 8). These differences cannot be ascribed to changes in body composition after cessation of GH treatment (5, 6, 7) at an average time of 1.6 yr earlier. If somatic development under GH replacement in childhood had been adequate, one would expect BMI and body composition values quantitatively comparable to those of AO GH-naïve subjects, which is not the case. In addition, we have seen that the net treatment effect of adult GH replacement on LBM and FM is quantitatively the same in CO and AO patients, and that the baseline differences between the two entities remains constant even when GH treatment is resumed in adulthood (8). On a height-normalized basis, CO patients have about 20% less total body mass, LBM, FM, and BMC than AO patients, whereas the percentage change in LBM and FM with GH replacement in an adult GHD subject is in the range of 3–8%. Furthermore, these differences cannot be explained away by the difference in mean age of the two cohorts (20.9 vs. 25.2 yr) because no more than 5% of LBM (14, 15) or BMC is acquired after the age of 20 yr (16, 17). We conclude that the different body composition of CO adult patients is a consequence of abnormal or incomplete development during childhood GH therapy.
Statistically significant correlations were found between final height SD score minus target height SD score and LBM and BMC in both females and males. LBM tends to start to rise in children at the age of about 10 yr, peaking at about 14 yr in girls and at 20 yr in boys (18). BMC is a reliable indicator of body maturity because the age of peak bone mineral accrual occurs about 1 yr after peak height velocity (16, 19). Complete muscle and bone maturation is, however, reached at a later stage, because LBM continues to increase for about 2–3 yr after epiphyseal fusion, and bone mass continues to accumulate for up to 7 yr after attainment of adult height (16).
Actual height SD score minus target height SD score correlation with FM was less clear: in males it was just significant (P = 0.045), and in females there was even a trend to a negative correlation. This may be explained by the variation in discontinuation interval that ranged up to 5 yr. On the other hand, this finding may also reflect the sexual dimorphism in fat accumulation during childhood and adolescence (20). Overall, the range of BMI in our CO group was consistent with that of the AO group across all obesity grades, which indicates that obesity in early adulthood is a consequence of CO GHD.
Although the height and body composition data overall confirm and expand previous observations, the IGF-I and IGFBP-3 data do add another dimension to the adult presentation of CO GHD. In both females and males, IGF-I and IGFBP-3 levels of CO patients who are off pediatric treatment are very significantly lower than those of GH-naïve AO patients of comparable chronological age. This is consistent with our previous findings (9) and also with data of De Boer et al. (21), who found that over 90% of a group of 89 young adult males who had completed childhood GH therapy had IGF-I and IGFBP-3 concentrations more than 2SD below the mean for age-matched controls. For the first time, we have demonstrated that these differences between the IGF-I and IGFBP-3 levels of CO and AO patients are present despite equal degrees of severity of GHD, allowing for the fact that the definition of GH status was dependent on provocative testing.
The difference in IGF-I and IGFBP-3 matches the differences seen between CO and AO in body composition. As a consequence, significant correlations between these measures and height and LBM in both CO and AO were found. The lack of statistical significance in the correlation between BMC and serum IGF-I or IGFBP-3 in AO subjects is probably due to the smaller number in this group but also to larger variation. In fact, after completion of normal pubertal development, each AO patient accrues peak bone mass in an individual manner until the onset of hypopituitarism and GHD, whereas in CO patients, bone maturation generally stopped at final height when GH therapy was withdrawn.
Compared with AO patients, CO patients are somatically retarded, with an IGF-I and IGFBP-3 system that has not reached full adult capacity. In normal adults, other factors in addition to GH contribute to IGF-I and IGFBP-3 levels. It would seem that these factors are absent in CO, and in this respect IGF-I and IGFBP-3 levels reflect underdevelopment rather than endogenous GH action alone. It appears that in adult patients there is an uncoupling of IGFBP-3 in particular from GH secretion, whereas other factors such as sex steroids, nutrition, or even kidney function may play a more important role than in childhood. Because there is a dependence of IGF-I levels on serum IGFBP-3, total IGF-I may show some uncoupling from GH.
The question arises how and when did the maturational gap in CO develop. At present, much attention is given to the so-called transition period, i.e. the phase of development, that occurs after the end of linear growth. Muscle and bone mass continue accumulating and reach adult values during this phase, and accordingly these events should be sustained by continued GH treatment. Indeed, many studies performed in GHD patients after withdrawal of pediatric GH underline this aspect (5, 22). Saggese et al. (23) concluded from a longitudinal study of childhood GH replacement that the adequacy of therapy during the childhood growth phase played a significant role in bone mass achieved by completion of growth and that GH treatment should be continued until the attainment of peak bone mass irrespective of the height achieved.
In the present assessment, we have studied a group of patients who have been severely GHD in childhood and remain so. Their clinical presentation significantly differs from that of AO patients, and the question is whether adequate GH replacement into adulthood will be enough to correct the differences. Some aspects of our comparison, such as the IGF-I and IGFBP-3 concentrations, are so impressive that we believe they may represent a more complex consequence of incomplete maturational events that have accumulated during childhood and adolescent development. The underdevelopment in the CO GHD patients is quantitative rather than qualitative, and therefore relative rather than absolute; body mass, both total and single compartments such as skeleton, muscle, and probably fat, are suboptimally acquired during childhood. Thus, there is a relative failure of anabolism in terms of achieving the genetically determined cell mass, tissue, and organ growth that should take place during development. If this is the case, existing algorithms of pediatric GH replacement therapy may have to be reassessed.
Acknowledgments
We are grateful for the assistance of the investigators involved in the study: Prof. M. Korsic (Croatia); Dr. J. Lebl, Dr. J. Zapletalova (Czech Republic); Prof. E. Keller, Dr. K. Mohnike, Prof. E. Schönau, Prof. N. Stahnke (Germany); Prof. F. Peter, Dr. G. Soltesz, Prof. J. Solyom (Hungary); Dr. G. Aicardi, Prof. E. Cacciari, Prof. G. Chiumello, Prof. C. De Sanctis, Prof. F. Severi (Italy); Dr. V. Peterkova (Russia); Dr. M. Paskova (Slovakia); Dr. C. Krzisnik (Slovenia); Dr. R. Gracia-Bouthelier (Spain); Dr. J. Gregory, Dr. I. McFarlane (United Kingdom); Dr. D. M. Brown, Dr. M. S. Eidson, Dr. C. Ganong, Dr. C. Gordon, Dr. C. A. Huseman, Dr. P. D. Lee, Dr. L. Levitsky, Dr. L. G. Linarelli, Dr. T. Moshang, Dr. R. Rapaport, Dr. D. R. Repaske, Dr. P. Saenger, Dr. B. D. Silverman, Dr. P. Speiser, Dr. H. Starkman, Dr. E. Tsalikian (United States).
Footnotes
Abbreviations: AO, Adult onset; BMC, bone mineral content; BMI, body mass index; CO, childhood onset; DEXA, dual-energy x-ray absorptiometry; FM, fat mass; GHD, GH-deficient or GH deficiency; LBM, lean body mass.
Received October 11, 2001.
Accepted March 7, 2002.
References
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