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Comparison of Continuation or Cessation of Growth Hormone (GH) Therapy on Body Composition and Metabolic Status in Adolescents with Severe GH Deficiency at Completion of Linear Growth

Department of Endocrinology (P.V.C., W.M.D., K.T.M., K.M., C.C.-H., M.O.S., J.P.M.), St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom; Department of Paediatric Endocrinology (N.J.S.), The Birmingham Children’s Hospital, Birmingham B4 6NH, United Kingdom; Department of Paediatric Endocrinology (D.B.D.), The John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; and Department of Paediatric Endocrinology (T.D.C.), The Royal Infirmary, Newcastle NE1 4LP, United Kingdom

Address all correspondence and requests for reprints to: P. V. Carroll, Department of Diabetes and Endocrinology, St. Thomas’ Hospital, London SE1 7EH, United Kingdom. E-mail: paul.carroll{at}gstt.nhs.uk.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Although GH replacement improves the features of GH deficiency (GHD) in adults, it has yet to be established whether cessation of GH at completion of childhood growth results in adverse consequences for the adolescent with GHD. Effects of continuation or cessation of GH on body composition, insulin sensitivity, and lipid levels were studied in 24 adolescents (13 males, 11 females, aged 17.0 ± 0.3, yr, mean ± SE, puberty stage 4 or 5) in whom height velocity was less than 2 cm/yr. Provocative testing confirmed severe GHD [peak GH < 9 mU/liter (3 µg/liter)] in all cases and was followed by a lead-in period of 3 months during which the pediatric dose of GH continued unchanged. Baseline investigations were then performed using dual-energy x-ray absorptiometry (body composition), lipid measurements, and assessment of insulin sensitivity by both homeostasis model assessment and a short insulin tolerance test. Twelve patients remained on GH (0.35 U/kg·wk), and 12 patients ceased GH treatment. The groups were followed up in parallel with repeat observations made after 6 and 12 months.

No endocrine differences were evident between the groups at baseline. GH cessation resulted in a reduction of serum IGF-I Z score [–1.62 ± 0.29, baseline vs. –2.52 ± 0.12, 6 months (P < 0.05) vs. –2.52 ± 0.10, 12 months (P < 0.01)] but values remained unchanged in those continuing GH replacement. Lean body mass increased by 2.5 ± 0.5 kg (6%) over 12 months in those receiving GH but was unchanged after GH discontinuation. Cessation of GH resulted in increased insulin sensitivity [short insulin tolerance test, 153 ± 22 µmol/liter·min, baseline vs. 187 ± 20, 6 months (P < 0.05) vs. 204 ± 14, 12 months (P = 0.05)], but no significant change was seen during 12 months of GH continuation. Lipid levels remained unaltered in both groups.

Continuation of GH at completion of linear growth resulted in ongoing accrual of lean body mass (LBM), whereas skeletal muscle mass remained static after GH cessation in these adolescents with GHD. This divergence of gain in LBM is of potential importance because increases in LBM occur as a feature of healthy late adolescent development. GH is a major mediator of insulin sensitivity, independent of body composition in adolescents. Further studies are required to determine whether discontinuation of GH in the adolescent with severe GHD once linear growth is complete results in long-term irreversible adverse physical and metabolic consequences and to determine conclusively the benefits of continuing GH therapy.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
CHILDREN WITH SEVERE GH deficiency (GHD) are treated with sc recombinant human GH to promote linear growth. On achievement of adult height, it has been traditional practice to discontinue GH replacement, and depending on the etiology of GHD, a decision is made whether ongoing evaluation is required in an adult clinical setting (1). It is now established that many adults with GHD develop a specific syndrome characterized by reduced psychological well-being, abnormal body composition, decreased bone mineral density and metabolic abnormalities contributing to increased cardiovascular risk (2, 3, 4). Epidemiological data indicate that adults with long-standing GHD have increased fracture risk and reduced life expectancy (5, 6, 7, 8). Although differences in the severity of symptoms among patients developing GHD in childhood as compared with adult life exist, convincing evidence indicates that many of the consequences of adult GHD are reversed with GH replacement even in those with childhood-onset GHD (2).

The precise evolution of the GHD syndrome after discontinuation of GH in adolescents whose linear growth is complete has not yet been established (9). Recently investigators have begun to study whether discontinuation of GH at adult height results in adverse consequences in the adolescent with severe GHD (10, 11). It is established that patients with childhood-onset GHD are shorter and have reduced lean body mass (LBM), compared with those that have acquired GHD in adult life (12). Evidence to date suggests that discontinuation of GH at completion of linear growth may result in adverse effects on body composition and lipoprotein levels, but there is controversy as to whether these abnormalities predispose to early atherosclerosis (13, 14, 15). As a result of the relative rarity of hypopituitarism and difficulties performing long-term studies in adolescents, the optimal approach to the management of GH treatment between cessation of linear growth and full adulthood has yet to be established.

To increase understanding of the complex role of GH in the regulation of the physical and metabolic changes of adolescent development in GHD, we performed this prospective U.K. multicenter study. At completion of linear growth, body composition, insulin sensitivity, and lipid levels were studied over 12 months in parallel groups of adolescent patients, either continuing or discontinuing GH, all of whom had confirmed ongoing severe GHD.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Twenty-four patients were recruited from growth clinics in the four contributing centers. The clinical details and etiology of GHD are summarized in Table 1. Thirteen males and 11 females aged 17.0 ± 0.3 yr, mean ± SE (range 14–20 yr), were included. Fourteen had multiple pituitary hormone deficiencies, and these patients were receiving stable substitution with hydrocortisone, L-thyroxine, sex steroids, and 1-desamino-8-D-arginine vasopressin as necessary. Patients with coexistent chronic disease, diabetes mellitus, or functioning pituitary tumors were excluded. All patients had been shown to have severe GHD and had been receiving GH for at least the previous 5 yr (and more than 8 yr in the majority) to promote linear growth. The patients were selected on the basis of achievement of adult height each having a growth velocity less than 2 cm/yr. Although we intended for this to be a fully randomized trial, a number of patients expressed a strong preference for either continuation or cessation of GH treatment. Accordingly, 70% of the patients included were randomized to continue or discontinue GH, with the remainder being treated according to individual preference.

Study protocol

In those willing to participate, GH was discontinued for 7 d before the performance of a provocative test of GH reserve (insulin-hypoglycemia; 0.15 U/kg iv was used in all but one patient who underwent a glucagon test; 1.0 mg sc). All patients had severe GHD, defined as a peak GH response less than 9 mU/liter (3 µg/liter) (18). Screened patients who had recovered GH secretion had GH treatment stopped and were not included in the study. A total of approximately 50 patients were considered for inclusion and underwent retesting, with severe GHD identified in the 24 included in the study. Therefore, in keeping with previous U.K. experience, recovery of GH secretion had occurred in half those patients previously identified as having GHD (19). In eligible patients the prestudy dose, which varied between individuals and centers, was recommenced for a 3-month lead-in before performance of baseline evaluations. In patients continuing GH, a standard dose of 0.35 U/kg·wk (0.12 mg/kg·wk) was self-administered (2200 h) in single daily doses. In those discontinuing GH, no placebo injection was used.

Measurements

Body composition, insulin sensitivity, and serum lipoproteins were assessed at baseline and 6 and 12 months in all subjects. Dual-energy x-ray absorptiometry was used to measure body composition. Baseline and follow-up scans were performed on the same instrument for each patient, and each machine underwent daily standard calibration using the appropriate manufacturer’s phantom. The software used were those employed as part of routine practice in the local centers. Either a Lunar DPX (General Electric, Madison, WI) or QDR-1000 (Hologic Inc., Waltham, MA) scanning system was used, depending on local availability, and data for whole-body LBM, fat mass (FM), percent FM, and truncal FM were produced using standard software.

Insulin sensitivity was measured using two techniques. Fasting specific plasma insulin and plasma glucose concentrations were used to calculate the percentage sensitivity (%S), a measure of whole-body insulin sensitivity (IS) using the homeostasis model assessment (HOMA) technique (20). Additionally whole-body IS was determined using a short insulin tolerance test (ITT) method (21). After an overnight fast, 0.1 U/kg iv soluble insulin was administered with frequent blood sampling for plasma glucose taken for up to 15 min. A linear plot of the slope of the glucose line taken from 3 to 15 min corresponded to IS, expressed as micromoles per liter per minute.

Serum total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and serum triglycerides were measured in the postabsorptive state on each occasion. Bone remodeling and bone mineral density data from these patient cohorts have been reported previously (22).

Laboratory assays

Laboratory assays were performed in the lead center (St. Bartholomew’s Hospital). Plasma glucose and serum GH were measured using standard automated techniques (Immulite 200, Diagnostic Products Corp., Gwynedd, UK). Serum cholesterol, HDL cholesterol, and triglycerides were assessed using conventional methodology for the AU 640 analyzer (Olympus Optical Co., London, UK). LDL cholesterol was calculated using Friedewald’s equation (23). Serum IGF-I was measured using an in-house RIA after formic acid-acetone extraction as previously described (24). Specific insulin was assessed using a commercially available immunoenzymatic assay (Biosource S.A., Fleurus, Belgium). Intra- and interassay coefficients of variation were 5.3 and 5.6%, respectively.

Statistical analyses

Data are expressed as mean ± SEM. Analyses were performed using Arcus Quickstat (Longman Software Publishing, Cambridge, UK). Comparisons were made within groups using the Student’s t test and between groups using Mann-Whitney U test. Correlations were performed using Spearman’s rank coefficient. P < 0.05 was considered significant.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
All patients continued in the study for the 12 months. No major adverse effects that were attributable to GH treatment occurred. No patient developed diabetes mellitus or recurrence of the original pituitary structural lesion or malignant disease.

Serum IGF-I

Individual serum IGF-I Z scores are shown in Fig. 1. The baseline IGF-I concentrations were widely variable at baseline in both groups. However, the baseline mean values for total IGF-I were similar between groups (337 ± 56, 257 ± 42, ng/ml, GH continuing and discontinuing, respectively; Z score –1.08 ± 0.38, –1.62 ± 0.29, GH continuing and discontinuing respectively).

View larger version (17K): [in this window] [in a new window]   FIG. 1. Serum IGF-I Z scores in severely GH-deficient adolescent patients continuing (GH +, n = 12) or discontinuing (GH –, n = 12) GH replacement [0.35 U/kg·wk (0.12 mg/kg·wk)]. *, P < 0.05, comparing baseline vs. 6 months. **, P < 0.01, comparing baseline vs. 12 months.

Body composition

Body composition values at baseline and throughout the study are summarized in Table 2. At baseline similar LBM, FM, percent fat mass, and truncal FM were observed between the groups. LBM increased during GH continuation but remained unchanged in those stopping GH treatment (Fig. 2). No significant changes in FM were recorded in either group.

View larger version (11K): [in this window] [in a new window]   FIG. 2. Percentage change in whole-body LBM in severely GH-deficient adolescent patients continuing (GH +, n = 12) or discontinuing (GH –, n = 12) GH replacement [0.35 U/kg·wk (0.12 mg/kg·wk)]. *, P < 0.05.

Baseline insulin sensitivity was similar between groups as assessed by either HOMA %S (Table 3) or the short ITT (Fig. 3). Insulin sensitivity as assessed by the short ITT increased significantly after GH cessation, but the trend in HOMA %S was not significant. No changes in IS were noted using either method in those remaining on GH replacement.

View larger version (15K): [in this window] [in a new window]   FIG. 3. Whole-body IS assessed using the short ITT in severely GH-deficient adolescent patients continuing (GH +, n = 12) or discontinuing (GH –, n = 12) GH replacement [0.35 U/kg·wk (0.12 mg/kg·wk)]. *, P < 0.05. **, P < 0.01.

Similar values for total cholesterol, LDL cholesterol, HDL cholesterol, and serum triglycerides were seen at baseline in both groups. No changes occurred throughout the study in any of these variables with either continuation or cessation of GH replacement (Table 3).

Relationships between variables

The change in IGF-I between baseline and 12 months (IGF-I) correlated with the change () in FM over the same period [P < 0.05, Spearman’s rank correlation coefficient (–0.54)]. A similar correlation was seen between IGF-I and %Fat at 12 months (P = 0.05, –0.43). A negative relationship was recorded between LBM and %S at 1 yr (P = 0.02, –0.56).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
A large number of studies have addressed the consequences of adult GHD, emphasizing the important role of GH in the maintenance of physical and psychological health (2). In contrast, relatively few studies have investigated whether GH regulates adolescent development in the phase between completion of linear growth and full physical maturity (10, 11, 12, 13). This lack of published data reflects the relative rarity of pediatric hypopituitarism and the inherent difficulties in performing longitudinal studies in adolescent patients. Advances in understanding of GH biology, coupled with recognition that patients with childhood-onset GHD have reduced skeletal muscle as adults (12), prompt reevaluation of the traditional practice of discontinuing GH in adolescents with GHD at achievement of adult height. The patients we studied were recruited from four of the largest neuroendocrine centers in the United Kingdom over a 3-yr period.

The baseline total serum IGF-I concentrations reflected real-life practice with a wide range of observed values across the group of patients. At commencement of the study, mean IGF-I concentrations were similar in those continuing and stopping GH treatment, with calculated Z scores beneath the mean value. The wide baseline variability was not related to the dose of GH before commencement of the study and may in part be explained by compliance issues, individual sensitivity to GH, estrogen use, body composition, and exercise activity. Although traditionally GH treatment in the pediatric population is not titrated against serum IGF-I levels, this U.K. population at baseline, while receiving GH treatment, did not have elevated IGF-I concentrations. Discontinuation of GH resulted in a marked reduction of IGF-I, reflected by a negative Z score, but continued GH at a dose of 0.35 U/kg·wk (0.12 mg/kg·wk) maintained IGF-I levels. Importantly, in those who remained on GH, similar levels of IGF-I (and Z score) were recorded at 6 months and 1 yr, supporting continuing compliance in this group. These baseline IGF-I values were similar to those reported in a study of Danish adolescents with GHD (25) but are substantially lower than a previously reported discontinuation study (14), perhaps reflecting national differences in pediatric GH dosing regimens.

Continuation of GH treatment was associated with gain in whole-body LBM at 6 and 12 months. In contrast, no net change in LBM was observed over 1 yr in patients discontinuing GH replacement. Although linear growth was virtually complete at entry to the study, it is unlikely that full skeletal and body compositional maturation had occurred by completion of our observations. At termination of the study, the patients were aged approximately 19 yr, and it is established that further gains in LBM continue until the age of 22–25 yr in the healthy population (26). It is of potential importance that GH cessation was associated with an absolutely static LBM, compared with the more normal 6% annual accrual seen in the group receiving GH. Previous studies have shown either reduced (27) or static LBM (13) after discontinuation of GH therapy in adolescents with GHD. In the latter study, recommencement of GH replacement after 12 months cessation resulted in approximately 16% increase in LBM over the following year. Decreased LBM has been reported after 24 months GH cessation in a Swedish population of adolescents with GHD; however, the baseline IGF-I concentrations reported in this study were high, and it is conceivable that the changes in body composition reflected previous supraphysiological treatment (14). In totality the available data indicate that LBM remains static or is moderately reduced after GH cessation in adolescents with GHD. In those remaining on GH, continuing increases in LBM are seen over 12 months after cessation of linear growth.

Although no changes in FM were demonstrated in either group, a previous study has shown increased FM after GH cessation in adolescents with GHD (13). In the latter study, increases in whole-body and abdominal FM were seen 12 months after discontinuation of GH, and resumption of GH treatment resulted in reduced FM. Increases in FM were also observed in both GHD and healthy adolescents in the Swedish GH withdrawal study over 2 yr (14). Although increases in FM may be a feature of healthy changes in body composition, the cumulative data provide evidence that adolescents with GHD are more prone to gains in adipose tissue. In our study it is possible that a 12-month period was too short for statistically significant changes to occur.

Increased IS occurred after cessation of GH treatment. It is recognized that adult-onset GHD is associated with relative insulin insensitivity, and GH replacement may worsen insulin sensitivity in the initial phase (28). Furthermore, concern has been expressed that GH administration in adolescents may exacerbate or cause type 2 diabetes mellitus (29). Within 6 months of GH cessation, increased IS was recorded using the short ITT, which was maintained at 12 months. These increases occurred despite a trend toward increased FM and no gain in LBM over the same period. In the current study, there was no significant change in HOMA %S, but a divergent trend was seen between the groups. Increases in IS were reported in a study of Danish adolescents with GHD after GH cessation (25). Using the hyperinsulinemic clamp technique, these investigators demonstrated similarly increased IS despite increased whole-body FM. In the present study, IS remained unchanged despite increased LBM and unchanged FM in subjects continuing GH replacement.

These complementary techniques comprehensively illustrate the importance of GH in the regulation of IS, independent of changes in body composition in the adolescent. However, whether the reduced IS while on treatment with respect to carbohydrate metabolism has adverse consequences has yet to be fully established. IS is reduced during normal puberty, in part related to increased endogenous GH secretion (30). It is conceivable that some of the anabolic effects on skeletal and LBM mass seen with normal puberty and during exogenous GH treatment are mediated through relatively decreased whole-body IS, resulting in increased insulin concentrations with consequent effects on protein and fat metabolism (31).

No striking effects on lipid levels were seen either during GH continuation or after GH cessation in these adolescent patients. Specifically, despite increased IS in those stopping GH treatment, no trends toward increased HDL cholesterol and reduced triglycerides were seen. In adults with GHD, reductions in LDL cholesterol have been documented during GH replacement (2). The unchanged serum lipid levels in the current study may be explained by the very normal levels at baseline and are similar to results reported in a previous study of adolescents with GHD (13). In contrast, other investigators documented increased LDL cholesterol and reduced HDL cholesterol after GH cessation in adolescent GHD (14). It is conceivable that the high IGF-I levels (reflecting a higher GH treatment dose) indicated a supraphysiological effect not observed in the current study in which lower doses of GH were administered. Divergent trends were not evident between those continuing and those stopping GH, suggesting that in these U.K. adolescents, GH was not a major mediator of serum lipid levels, at least in the short term. These data indicate that the elevated LDL/reduced HDL cholesterol pattern characteristic of GHD in adults evolves over a period in excess of 12 months and involves more than acute alterations in IS and body composition.

This study included patients with organic structural pathologies accounting for hypopituitarism and adolescents with idiopathic GHD. No clear differences in baseline characteristics were demonstrable depending on etiology. Similarly, the response to continuation/discontinuation was not evidently different between these populations.

It is not known whether cessation of GH treatment at achievement of adult height results in long-term adverse consequences for the adolescent with ongoing GHD. In practice GH replacement is frequently discontinued, and long-term GH replacement may not be reconsidered until the transition from pediatric to adult endocrine care is complete. This U.K. multicenter study indicates that accrual of LBM continues in patients remaining on GH replacement after completion of linear growth. In contrast, LBM remains unchanged despite increased insulin sensitivity over 12 months after GH cessation. These differences in skeletal muscle development are of potential importance because it is recognized that patients with childhood-onset GHD have reduced LBM, compared with those with adult-onset hypopituitarism. Additionally, continued gains in LBM are a feature of healthy physical development after linear growth ceases.

We advocate retesting adolescents with severe GHD requiring GH treatment to promote growth once adult height is achieved. Those patients with ongoing severe GHD should be considered for continuation of GH replacement. Large multicenter longitudinal studies will be necessary to determine whether the differences in LBM accrual between those continuing and those stopping GH treatment contribute to reduced physical and psychological health in adulthood and whether there is a critical duration of cessation of GH therapy after which the response to GH replacement is reduced.

	Acknowledgments

 
We are grateful for excellent nursing support in all of the centers. Pharmacia Corp. supplied the GH used in this study.

	Footnotes

 
This work was supported by an unrestricted research grant to the Department of Endocrinology at St. Bartholomew’s Hospital from Pharmacia Corp.

Abbreviations: , Change between measures; FM, fat mass; GHD, GH deficiency; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; IS, insulin sensitivity; ITT, insulin tolerance test; LBM, lean body mass; LDL, low-density lipoprotein; %S, percentage sensitivity.

Received September 11, 2003.

Accepted April 30, 2004.

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