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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0208
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 3946-3955
Copyright © 2005 by The Endocrine Society

Limited Efficacy of Growth Hormone (GH) during Transition of GH-Deficient Patients from Adolescence to Adulthood: A Phase III Multicenter, Double-Blind, Randomized Two-Year Trial

Nelly Mauras, Ora Hirsch Pescovitz, Vivek Allada, Michael Messig, Michael P. Wajnrajch, Barbara Lippe on behalf of the Transition Study Group

Division of Endocrinology (N.M.), Nemours Children’s Clinic, Jacksonville, Florida 32207; Department of Pediatrics (O.H.P.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Pfizer (M.M., M.P.W., B.L.), New York, New York 10017; and Department of Pediatrics, University of California, Los Angeles (V.A.), Los Angeles, California 90095

Address all correspondence and requests for reprints to: Nelly Mauras, M.D., Chief, Division of Endocrinology, Nemours Children’s Clinic, 807 Children’s Way, Jacksonville, Florida 32207. E-mail: nmauras{at}nemours.org.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Treatment of GH-deficient adolescents in transition to adulthood remains challenging.

Objective: The objective was to assess the safety and efficacy of GH in GH-deficient adolescents in transition.

Patients: Fifty-eight GH-deficient adolescents (mean age, 15.8 ± 1.8 yr; 33 males) at near completion of their linear growth participated in the study.

Intervention: Baseline studies were done while subjects were on GH. Subjects were retested (insulin-induced hypoglycemia) 4 wk after GH discontinuation and reclassified as persistently GH-deficient or controls (n = 18). GH-deficient subjects were randomized to GH (n = 25, ~20 µg/kg·d) or placebo (n = 15).

Setting: The multicenter study was conducted over a 2-yr period.

Main Outcomes: Changes in body composition, bone mineral density (BMD), quality of life (QOL), cardiovascular and metabolic markers were measured.

Results: All groups had normal measures of lipid and carbohydrate metabolism, body composition, BMD, cardiac function, muscle strength, and QOL at baseline and after 2 yr. IGF-I concentrations decreased in all, but less so in the GH-group (P = 0.013). There was a greater increase in lean body mass (lesser adiposity) in the GH group than placebo at 12 months, but not at 24 months.

Conclusions: 1) GH-deficient patients properly treated in childhood can have normal BMD, body composition, cardiac function, muscle strength, carbohydrate and lipid metabolism, and QOL when reaching adult height; and 2) continuation of GH therapy for 2 yr did not change these measures as compared to placebo-treated or control subjects. GH-deficient adolescents in good metabolic status at the time of epiphyseal fusion may safely discontinue GH for at least 2 yr. Follow-up is needed to determine whether GH therapy is eventually warranted in subjects treated with GH during childhood.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE APPROACH TO the treatment of GH-deficient subjects in the transition from adolescence to adulthood is an area of importance in contemporary endocrinology. A large cohort of youngsters has been treated with GH for the diagnosis of GH deficiency as children with the predominant goal to achieve a taller height. When adult height was achieved, it was customary to discontinue GH administration. Over the last several years, however, a number of published papers suggested that the actions of GH are far more complex than stimulating linear growth, with potent effects promoting lipolysis, lean body mass accrual, bone mineralization, normal cardiac function, exercise tolerance, and even quality of life (QOL) (1, 2). A well-defined profile of GH deficiency syndrome in the adult evolved, prompting the approval of GH replacement in adults with this syndrome in the United States, Western Europe, Australia, and Japan. Because adult body composition, peak bone mass, and maximal muscle strength may not be achieved until the mid-20s in males, the concept of the adolescent in transition to adulthood evolved. Previous multicenter trials have examined the use of GH in this patient population using several study protocol models. In some, subjects were recruited a few years after GH discontinuation; in others, subjects remained on GH at the completion of final adult height. Some studies involved placebo-controlled vs. open-label models, and some used one or two different GH doses for either 1 or 2 yr of treatment. These trials have yielded somewhat mixed results (3, 4, 5, 6, 7, 8, 9, 10). Lean body mass and bone mass accrual were shown to be better in those severe GH-deficient patients in whom GH therapy was continued vs. those in whom it was discontinued, but individuals who had been off GH a mean of 1.3 yr (range, 6 wk to 5 yr) were shown to still accrue bone mass very well after reinitiation of treatment (7).

Extensive research on the effects of GH deficiency and GH replacement therapy on QOL during adolescence and early adulthood has yielded somewhat equivocal results, especially with respect to patients treated for childhood-onset GH deficiency (11, 12). Therefore, the present study also included serial measurements of several dimensions of QOL that have proven sensitive to GH deficiency or GH replacement therapy in other studies. These dimensions include general health-related QOL, social adjustment, and aspects of QOL that are specific to GH deficiency (13).

The issue of proper dosing also became important in the GH-deficient adolescent in transition, and it became clear that if GH was to be continued, the doses of GH used might need to be intermediate between those used during childhood treatment and adult replacement. This concept is also consistent with the fact that GH production rates markedly decline after the achievement of adult height but are higher than those of older adults (14). Adolescents and young adults with GH deficiency have received a wide range of GH doses during the transition period, lower than childhood treatment yet higher than adult replacement. Those receiving doses of 25 µg/kg·d performed better than those getting 12.5 µg/kg·d in some studies (8), but there was not a clear dose effect in other studies (7, 10).

The primary objective of the present study was to establish the efficacy regarding body composition and bone mineral density (BMD) changes, as well as the safety, of a transition dose (20 µg/kg·d) of GH (somatropin, rDNA origin) as replacement therapy in subjects with profound GH deficiency during the transition from adolescence to adulthood. We also designed the study to explore, as secondary objectives, the effects of GH treatment on plasma lipids, IGF-I concentration, carbohydrate metabolism, cardiac function, exercise tolerance, and QOL. The experimental design also allowed us to further evaluate the frequency of persistent GH deficiency after retesting at the time of therapy cessation. We designed these experiments in a multicenter, double-blind, placebo-controlled 2-yr follow-up format in subjects who were treated for GH deficiency as children and who upon re testing were still GH deficient. Subjects who were GH sufficient at retesting served as untreated controls.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
These studies were approved by the individual institutional review boards of each participating center and were carried out after written informed consent from the subjects and parents (when appropriate). The study was a randomized, double-blind, placebo-controlled treatment trial of 24 months duration.

Inclusion/exclusion criteria

Patients who carried the diagnosis of GH deficiency in childhood and who were treated with GH for at least 3 yr before these studies, with an average dose of approximately 0.3 mg/kg·wk (or 42 µg/kg·d), were recruited for participation. Persistence of GH deficiency was defined as peak GH response to an insulin-induced hypoglycemia tolerance test (ITT) of less than 5 µg/liter as measured by a polyclonal RIA in a centralized laboratory. We chose this cutoff because we were targeting the study of adolescents who, compared with adults, have much greater GH secretory capacity. We defined as a requisite for adequate hypoglycemia during the test a fall in blood glucose by 50% of fasting and/or to less than 50 mg/dl. Subjects had achieved final height as defined by growth velocity of less than or equal to 2.5 cm/yr (annualized from growth over the previous 6-month period) and a bone age of at least 14.5 yr in girls and at least 16.5 yr in boys. All subjects were fully pubertal, defined as either spontaneous menarche in girls and Tanner stage IV or greater genital development in boys. If puberty was medically induced, girls were treated with cyclic estrogen/progesterone therapy and boys were treated with 200 mg testosterone monthly for at least 3 months before the study. The recommended sex steroid regimens remained unchanged throughout the 24-month study period.1 All subjects had normal thyroid function at baseline and for those on thyroid hormone replacement, doses were titrated by their endocrinologists during the study to maintain euthyroidism. Subjects with chronic illnesses, total body or spinal irradiation, or complex syndromes of GH deficiency (which could affect bone, body composition, cardiac function, or cognitive function) were excluded from participation. Subjects with a history of malignancies or tumors had no evidence of recurrence for at least 1 yr before participation.

Study design

The study consisted of three phases: a basal phase, a washout phase, and an assessment phase.

Basal phase. While still taking GH, all subjects underwent basal studies including IGF-I, IGF-binding protein (IGFBP)-3, osteocalcin, deoxypyridinolines, fasting total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoproteins A1 and B, fasting glucose and insulin, as well as HbA1c, free T3, and free T4, and testosterone level (in males only). In addition, dual-energy x-ray absorptiometry (DEXA) scanning was performed to assess body composition and BMD. An echocardiogram and an exercise test were done to assess cardiac function. Three QOL questionnaires were performed. A medical history and complete physical examination, injection site and neurological examinations, waist-hip and skin-fold measurements, and grip strength dynamometer tests were also performed.

Washout phase and study entry. After the basal study, GH was discontinued in all subjects and after 1 month, a standardized GH test (ITT) and a repeat of the GH/IGF axis panel were conducted. Whether or not a subject was randomized to double-blind study treatment depended upon the ITT results. Those subjects meeting the protocol-specified criteria for GH deficiency were eligible for randomization to double-blind treatment with either Genotropin (Pfizer, Inc.) at 0.14 mg/kg·wk divided into six or seven weekly doses (~20 µg/kg·d) or placebo (2:1 ratio). Those who did not meet the criteria for GH deficiency based on their response to GH provocative testing were recruited to participate as untreated controls.

Assessment phase. Subjects randomized to double-blind study treatment were followed for 2 yr on a schedule of 2, 4, 8, 12, 16, 20, and 24 months. The untreated controls were assessed only at 12 and 24 months after the provocative GH test. Extensive safety data were also collected in all subjects. Patients were instructed to return their empty cartridges at each subsequent office visit to monitor compliance.

Patients who received double-blind placebo therapy in the trial were offered the opportunity to continue in an open-label treatment study (for 2 yr) upon its completion. Figure 1Go shows a schematic summary of the experimental design.



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  		FIG. 1. Schematic design of the experimental procedures. Arrows represent main study visits with DEXA and full cardiovascular exams as well as all other study end points. mo, Months.

 
Assays

IGF-I, IGFBP-3, GH, testosterone, thyroid hormone concentrations, and osteocalcin were measured by RIA at Esoterix Laboratories (Calabasas Hills, CA). Plasma lipids and blood chemistries were measured by automated analyzers. Glucose and HbA1C were measured by hexokinase methods and an immunoturbidimetric assay, respectively.

Anthropometrics measures

The sum of skin folds (subscapular, abdomen, triceps, and medial calf) was used to estimate body composition in the interim visits when DEXA was not performed. Waist-to-hip ratio was also measured.

DEXA

Hologic QDR instruments (1000, 2000, or 4500 series; Hologic, Waltham, MA) were used to measure bone mineral contents at the lumbar and whole-body levels. Standardization procedures were carried out using a single phantom for calibration at all participating sites. Data were analyzed at a central location (Hologic) and reported as Z scores for BMD. The fat-free mass and percent fat mass were also recorded using the instruments’ software.

Echocardiography and Doppler evaluation

Two-dimensional, pulsed Doppler, and M-mode echocardiography studies were performed at each site in accordance with American Society of Echocardiography standards (15) and nomenclature (16, 17) and recorded on VHS cassette tape for review at the central review site by a single pediatric cardiologist (V.A.). For each measurement, at least three cardiac cycles were recorded. The following measurements were made by M-mode: left ventricular (LV) internal diameter at end-diastole and end-systole, posterior wall thickness, interventricular septal thickness. Measurements made by pulsed Doppler (cm/sec) were mitral inflow velocity [maximal early diastolic flow velocity (peak E wave)], maximal late diastolic flow velocity (peak A wave), and isovolumic relaxation time.

Exercise testing of cardiovascular performance

Treadmill testing was performed using a Bruce protocol in accordance with the American Heart Association guidelines for exercise testing in the pediatric age group (18) and exercise standards (19) using manual cuff blood pressure with manual sphygmomanometer and stethoscope. A 12-lead electrocardiogram was performed at rest and at each stage of the Bruce protocol. Exercise duration times were recorded as Z scores based on established normal data (20).

Grip strength measurements

This was measured using a handgrip strength dynamometer at the elbow, flexed to 90° with the forearm and wrist in the neutral position. The patient was instructed to squeeze until the peak strength pointer no longer advanced. Three measures were taken with 60-sec rest between each measure.

QOL questionnaires

In an effort to capture effects on QOL attributable to resumption of GH replacement therapy, subjects in all three groups completed three questionnaires that were selected on the basis of their potential sensitivity to the domains of daily functioning that have been implicated in other studies. The Medical Outcomes Study SF-36 (21) was selected as a measure of general health-related QOL because it has been shown to possess stronger validity than other comparable measures (22). The Growth Hormone Deficiency Disease-Specific Questionnaire (GHD-DSQ) was developed and validated by the study sponsor (Pfizer/Pharmacia) for use in this and other GH deficiency research (23). It consists of 25 items that require subjects to respond with yes or no regarding whether a given statement is true of them. The number of yes responses serves as the total score, with higher scores indicative of worse QOL. The Social Adjustment Scale Self Report Questionnaire (SAS-SR) was selected as a measure of patients’ social adjustment in the contexts of work, family relationships, and social/leisure activities (24). Raw scores for each domain were transformed to standardized T scores (mean = 50; SD =10) using available norms, and T scores were then categorized conservatively as indicative of significant problem (>66), possible significant problem (60–66), possible concern (40–59), and no concern (<40).

Statistical analysis

The intent-to-treat population included all patients who were randomized to one of the two treatment groups or were enrolled as GH-sufficient controls. All efficacy analyses were performed using the intent-to-treat population. The evaluable population for QOL included all patients who were competent to complete the questionnaires. Three subjects in the control group were excluded from the analysis of the measured outcomes because they had multiple anterior pituitary hormone deficiencies.

Categorical variables were summarized with frequency distributions and percentages. For continuous variables, mean ± SEM, median, and range (minimum to maximum) were reported. All inferential analyses were performed using analysis of covariance (ANCOVA) models. Inferential analyses for IGF-I and IGFBP-3 were performed on the rank scores. All hypothesis tests were conducted using a two-sided type I error rate of 5%.

Calculations

Measures of insulin resistance, the homeostasis model assessment (HOMA), and sensitivity, QUICKI, were calculated using the following formulas: HOMA = [fasting insulin (µU/ml) x glucose (mg/dl)]/22.5 x 18 (25); and QUICKI = 1/[log (fasting insulin (µU/ml)) + log (fasting glucose (mg/dl)]/18 (26).

Calculations of systolic and diastolic function were derived using previously described formulas (15). Normal LV mass for males was considered less than 103 g/m2, for females 84 g/m2 (17). As an index of LV diastolic function, mitral early inflow/atrial inflow (E/A) ratio was calculated: E/A = peak E velocity/peak A velocity (normal E/A, >1).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
All 58 screened subjects were enrolled into this study at 14 U.S. centers; 25 were enrolled in the GH group, 15 in the placebo group; 18 of the 58 were considered GH sufficient upon retesting. Forty-two completed the 24-month study period: 21 (84%) patients in the GH group, 11 (73%) in the placebo group, and 10 (56%) in the GH-sufficient control group. Tables 1Go and 2Go summarize the patient characteristics of the study subjects. All subjects in the GH-sufficient group experienced spontaneous puberty, and approximately three quarters in the GH- and placebo-treated groups did. All subjects were fully pubertal at study entry. Three subjects in the GH-treated group were on physiological, stable replacement doses of oral glucocorticosteroids for ACTH deficiency. Three subjects in the control group who completed the study were excluded from analysis because they had evidence for multiple anterior pituitary hormone deficiencies, and hence we believe they should not be considered true controls.


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  		TABLE 1. Subjects’ demographics

 

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  		TABLE 2. Etiology of GH deficiency

 
IGF-I/IGFBP-3

The median (range) IGF-I values at the basal visit were similar between all subjects in the GH-deficient group (GH-treated and placebo) and control groups [407 ng/ml (69–821) vs. 470 (240–644); P = 0.103]. The IGF-I concentrations declined over the 24 months of the trial in all groups, but this decline was much less in the GH treatment group (Table 3Go). The change from basal IGF-I values for the male population was much larger for the placebo and control groups than the GH-treated group at months 12 and 24. This same pattern was not observed for the female population (Fig. 2Go).


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  		TABLE 3. IGF-I and IGFBP-3 concentrations

 


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  		FIG. 2. Changes in IGF-I concentrations, expressed as percent change from baseline in all three study groups in females, males, and combined groups. *, P < 0.05 vs. placebo.

 
The median IGFBP-3 values at the basal visit were lower in the GH-deficient group (GH-treated and placebo) compared with controls (3.7 vs. 4.3 mg/liter; P = 0.016, respectively). The change in IGFBP-3 from basal to month 24 was significantly different between the GH- and placebo-treated groups (–0.1 vs. –0.7 mg/liter; P = 0.008).

Body composition

There were no statistically significant differences found across groups for change in weight and body mass index at any of the time points (data not shown). There were no differences in mean percentage of body fat at the basal visit, which was 23% for both the GH-deficient and -sufficient (control) subjects. As expected, the percent body fat for the female population was, on average, higher than the male population, 30 vs. 18% for the GH-deficient group and 28 vs. 18% for the GH-sufficient group. The mean percentage of lean body mass was the same, 74% for the GH-deficient (GH-treated and placebo) and -sufficient patients. There were changes in body composition over time in all three groups with overall increases in adiposity and decreased lean body mass. The mean change from basal to month 12 in percentage of body fat was significantly smaller in the GH-treated group compared with the placebo group (2.4 ± 1.0 vs. 6.0 ± 1.3; P = 0.022, respectively). Patients in the placebo group had a greater decrease in lean body mass from the basal visit to month 12 compared with the GH-treated group (P = 0.025). However, these changes were not sustained at 24 months, with no differences in percent body fat or lean body mass among the three groups when comparing 24 months vs. basal and 24 vs. 12 months. The changes in body composition are displayed in Table 4Go.


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  		TABLE 4. Body composition measures

 
There were no significant changes in waist-to-hip ratio from basal to month 24 in males or females in either treatment group (data not shown).

BMD

Table 5Go summarizes the changes in BMD Z scores during the trial. There were no significant differences across the three groups in any of the BMD end points, including lumbar spine and whole-body scans. There were no differences in the rate of increase of the BMD over the 2 yr of follow-up in any of the three treatment groups.


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  		TABLE 5. BMD Z scores

 
Echocardiography and Doppler evaluation

Evaluation of cardiac function was performed by two-dimensional and Doppler echocardiography. LV systolic function as measured by shortening fraction was essentially normal in all subjects at baseline and did not show any significant differences between GH-deficient and controls at the basal visit. All subjects had a shortening fraction that was greater than or equal to 28%. A test of the change in shortening fraction was not statistically significantly different across groups for the basal and month 12 (P = 0.508) or basal and month 24 comparisons (P = 0.345). The LV mass at the basal visit was similar between the GH-deficient (GH-treated and placebo) and control subjects (P = 0.245). The LV mass for the female population was, on average, lower than the male population, 61 vs. 67 g/m2 for the GH-deficient group and 64 vs. 75 g/m2 for the control group. One subject in the control group exceeded the upper 95% confidence interval of the gender-specific reference population at basal state and throughout the study. Whereas there was one female in the GH treatment group whose LV mass increased above the normal range by month 24, overall, there were no changes in LV mass during the study with no significant differences across groups for either the basal vs. 12-month or 24-month comparison. There were no significant differences in isovolumic relaxation time among the groups with no change between basal and month 12 (P = 0.215) or basal and month 24 (P = 0.318). One subject, who was in the GH-deficient group, exceeded the upper 95% confidence interval of the gender-specific reference population during the study. One patient in the GH treatment group had abnormal isovolumic relaxation times during the study that normalized by month 24. The E/A ratio is a global assessment of diastolic function, with normal levels being greater than one. There were no significant differences across groups detected for the change in E/A ratio for basal vs. month 12 (P = 0.749) or basal vs. month 24 (P = 0.328). The isovolumic relaxation time, shortening fraction, and E/A ratio also did not show any statistically significant differences between GH-deficient and control patients during the basal visit. All subjects had a shortening fraction that was greater than or equal to 28% and all but two, who were in the control group, had an E/A ratio greater than one.

Exercise testing of cardiovascular performance

The mean treadmill exercise tolerance Z score at the basal visit was similar between the GH-deficient and control groups (P = 0.987). The Z score for the female population was, on average, higher than the male population, 2.2 vs. 1.6 (P = 0.292) for the GH-deficient group (GH-treated and placebo) and 2.4 vs. 1.3 for the control group (P = 0.161). There were no other gender differences in the summary statistics. The change in treadmill exercise tolerance Z scores showed statistically significant differences between the groups at 12 months (P = 0.036), with a greater decrease in exercise tolerance in the GH-treated vs. placebo-treated groups (P = 0.013), although the absolute difference in mean exercise duration from basal to the 12-month time was only a mean decrease in 1 min. This difference was not significant at 24 months, however. Furthermore, the number of patients that decreased exercise duration from basal to 24 months was similar in all three groups (treatment group, 47%; placebo, 38%; control group, 50%).

Grip strength measurements

There were no statistically significant treatment differences detected in grip strength for either gender at any of the visits. There were no changes at baseline among the groups either (data not shown).

Lipids/carbohydrate metabolism

There was no significant difference in fasting glucose concentrations or in measures of insulin resistance (HOMA) and insulin sensitivity (QUICKI) in any of the groups at baseline or throughout the 24 months of the trial (data not shown). There were no significant differences across groups for any of the lipid end points, including total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol, total/HDL cholesterol ratio, and triglycerides at baseline or for the basal vs. month 12 or basal vs. month 24 comparisons (data not shown).

QOL

Mean basal QOL scores for the two measures with available normative data (SF-36 and SAS-SR) revealed that none of the three groups’ scores differed significantly from the normative means for either measure. In aggregate, none of the groups reported more serious QOL difficulties than is true of the general population upon study entry. Normative data are not yet available for the GHD-DSQ.

There were no significant differences in mean total scores or in change in scores relative to the basal score from basal to 12 months or from basal to 24 months for either the total scores or subscale scores of the SF-36 or the SAS-SR. For the GHD-DSQ, mean change in total score did not differ significantly between groups, i.e. from basal to 12 months or from basal to 24 months. When the four GHD-DSQ subscale scores were analyzed, a significant between-group effect was obtained (P < 0.015). Post hoc comparisons indicated that the GH-treated (P = 0.034) and placebo-treated (P = 0.005) groups both differed significantly from the control group on the physical function subscale. Both of the former groups had GHD-DSQ scores for physical function that were more favorable than those of the control group at 24 months (P = 0.041).

Safety

A comparable proportion of treated and untreated GH-deficient subjects reported adverse events during the 24 months of the trial (92% in the GH-treated group, 87% in the placebo group), whereas 72% of the subjects in the control group reported adverse events. Of these events, only one in each of the GH-treated and placebo groups was considered to be a drug-related adverse event. The most prevalent adverse events experienced were headache, nasopharyngitis, nausea, and sinusitis. Two subjects in the placebo group experienced adverse events thought to be drug related; one subject in the GH-treated group experienced edema, and one in the placebo group experienced increased sluggishness. Two subjects in the placebo group experienced serious adverse events. These events included convulsion, depression, and intentional self-injury. No significant cardiac side effects were noted.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The randomized, placebo-controlled nature of this study and the strict inclusion criteria allow for a detailed analysis of the use of GH in the GH-deficient adolescent who is no longer growing but who is yet to achieve full adult body composition. Although some of our findings have been reported before by others, several important and novel observations also arise from these studies. First, we observed that, compared with placebo, there was no significant beneficial effect of GH on measures of either body composition or bone mass over the 2 yr of study. There were also no measurable improvements in functional measures of muscle strength. IGF-I concentration decreased in all subjects, but the decrease was much less in the GH-treated individuals, as would be expected, a trend that paralleled the changes in IGFBP-3 concentrations. We did not titrate the dose of GH based on IGF-I concentrations because this would have required a more complex experimental design. Detailed cardiovascular assessment revealed normal cardiac function and exercise tolerance in the study subjects at baseline and throughout the trial duration. The lipid profile did not change during GH therapy, and measures of carbohydrate metabolism showed only mild increases in measures of insulin resistance. Measures of QOL were unchanged by intervention during the 24-month trial.

Body composition

A body of reported data in the literature has shown beneficial effects of GH replacement therapy in adults (1, 2, 26, 27, 28, 29), including decreased percent body fat and increased lean body mass, both related to a decrease in cardiovascular risk factors. These data forced the reappraisal of the standard practice in pediatric endocrinology of discontinuing GH therapy in GH-deficient youth once their linear growth and epiphyseal fusion were completed. However, studies specifically addressing the benefits of GH replacement therapy in adolescents who have finished growing, considered to be in transition, have so far yielded somewhat conflicting results. A small cohort of 11 adolescent subjects with GH deficiency had a decrease in resting energy expenditure and an increase in adiposity within a few weeks after discontinuation of GH, effects sustained for 1 yr of observation and not detected in healthy controls (30). Vahl et al. (4) studied 19 adolescents with childhood-onset GH deficiency at the time of discontinuation of treatment, followed for 1 yr on either placebo or GH and then another year on GH in all subjects. They observed a significant increase in percent body fat after 1 yr in the placebo-treated group and no change in the GH-treated group. Attanasio et al. (5), in a large cohort of multinational subjects, showed a significant decrease in adiposity with GH treatment in adolescents in transition but no dose effect (12.5 vs. 25 µg/kg·d), yet a marked gender effect, with much more robust responses in males. However, Johannsson et al. (31) reported no changes in percent body fat over 2 yr in healthy controls, whereas persistently GH-deficient subjects had a more significant increase in percent fat mass 2 yr after discontinuation of treatment than those who discontinued treatment but upon retesting were considered GH sufficient. These differences in increased adiposity in GH-deficient adolescents were subtle and not dissimilar from what we are reporting here. In our study, we observed that all three groups, GH-treated and placebo-treated GH-deficient subjects as well as controls, had a significant increase in percent fat mass over the 2 yr of the study. Although the increase was less in the GH-treated group than those treated with placebo, these differences were not sustained at 24 months. This lack of improvement after 2 yr may also be a result of the sustained decrease in GH dosing (relative to the dose given during active growth).

BMD

Previous studies have suggested that adult GH-deficient subjects of both adult and childhood onset have lower BMD than healthy controls (32, 33, 34, 35). The bone-anabolic actions of GH have been extensively studied, and the impact of GH on bone mass accrual can continue even after discontinuation of therapy for over 1.5 yr (36). In an open-label trial, Drake et al. (6) randomized GH-deficient adolescents in this transition phase to GH treatment or observation and recorded a greater percentage of BMD accrual with GH. Additionally, continuation of GH therapy for 2 yr in adolescents in transition resulted in greater bone mass accrual rates in those treated with higher GH doses (25 µg/kg·d), although those on placebo also accrued bone mass (7). We demonstrated no differences in BMD accrual response in GH-deficient patients treated with GH vs. those that received placebo. However, compared with a healthy, non-GH-treated population, the Z scores at baseline were normal in both the GH-deficient group and the controls. This suggests that GH therapy in GH-deficient children can normalize bone mass in adolescence and that the accrual of bone mass can continue after the completion of linear growth, even without GH, for at least 2 yr.

Lipids/carbohydrate metabolism

Data thus far have offered inconsistent results regarding the effects of GH on plasma lipid concentrations, both in adults and in adolescents (1, 2). Several studies have shown no improvement in lipid markers after either discontinuation or reinitiation of GH therapy in this period (4, 5, 31). Those data are different from those reported by Colao et al. (37) in a much smaller cohort of subjects but congruent with the lack of sustained benefit after 24 months observed in adults with childhood-onset GH deficiency treated with GH (8). Similarly, we showed no difference in lipid profiles in the GH-treated group.

In the present study, we observed no changes in any measures of carbohydrate metabolism or in global measures of insulin sensitivity in GH-treated vs. placebo-treated and control subjects. This is similar to much of the reported data in this age group (3, 4, 8, 9, 31). However, GH therapy can be associated with mild hyperinsulinemia yet normal glucose concentrations. Using hyperinsulinemic euglycemic clamps in adolescents with GH deficiency in the transition phase, Norrelund et al. (3) showed a significant increase in insulin sensitivity in the placebo-treated group compared with the GH-treated group, suggesting that continued GH treatment does not overcome the insulin-antagonistic effects of GH over time.

Muscle strength

Administration of GH or withdrawal of GH in this cohort of GH-deficient adolescents in transition was not accompanied by any significant changes in skeletal muscle strength. Although our measure of strength (hand grip) may well be inadequate to demonstrate subtle changes in efficacy, it was an easy-to-use, reproducible tool, convenient for a multicenter trial. The results are, however, similar to those reported in adults both short and long term (29, 8) and similar to those observed in trials of younger adolescent subjects (4).

Echocardiography/exercise

The current study showed no significant detrimental effects of GH therapy on cardiac parameters of resting systolic and diastolic function in the treatment group. However, no significant beneficial effects could be shown over the 24-month period either. The data are reassuring and suggest that GH-deficient children replaced with GH (i.e. using GH doses of ~0.3 mg/kg·wk) have normal cardiac function at the completion of linear growth. Colao et al. (37) showed a mild decrease in cardiac function in a group of GH-deficient adolescents in transition; however, the group was small and uncontrolled, and the cardiac parameters were still within the normal range. Our results are, however, similar to the reports from other trials using GH in the transition to adulthood where no substantial changes in cardiac function were observed in childhood-onset GH-deficient adults, with or without treatment (8).

QOL

The results of studies on QOL in GH deficiency have been conflicting, some showing an improvement of some aspects of QOL, whereas others show no difference with GH replacement (4, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54). When specific tools designed for use in the GH-deficient state were used, GH replacement appears to improve QOL measures (12); however, these findings appear to be mostly in adult-onset GH-deficient states. The effects of GH replacement therapy on QOL were minimal in our study, similar to other reports (8). It is possible that the detection of potential beneficial effects of GH replacement therapy on QOL may have been impeded because the therapy yielded few discernible physiological benefits, and more importantly, the study sample had basal QOL scores that were indistinguishable from those of the general population, possibly reflecting the positive impact of several years of GH treatment in childhood. Taken in aggregate, however, our data support the conclusion that discontinuation of GH therapy for 2 yr in the transition from adolescence to adulthood does not have deleterious effects on global measures of well-being and QOL and that GH replacement does not alter the state achieved at discontinuation of treatment.

Summary

What might be the difference between our lack of positive results treating GH-deficient adolescents in transition and the beneficial effects reported in adults with GH deficiency? The dose of GH chosen (~20 µg/kg·d) is likely not an explanation because it is an intermediate dose between that used in adults vs. in growing children. Also, there was no apparent dose effect in previously treated adolescents in the transition phase (10). The role of gender could be a factor because males appear to be more sensitive to GH replacement than females, even in the adolescent-to-adulthood transition phase (10). Analysis of our data by gender, however, yielded comparable results in males and females. We postulate that a more likely explanation for the lack of substantial changes observed after 2 yr of GH replacement might be the time elapsed since discontinuation of GH. Underwood et al. (8) showed a marked improvement in lean body mass and decreased adiposity in GH-deficient subjects treated with GH as children. However, this cohort was much older (mean age, 23.8 yr) and had been off GH an average of 5.6 yr. Lastly, we did not use the IGF-I concentrations as a criteria for inclusion into the study. It is possible that a greater effect of GH treatment would have been observed in subjects with severe GH deficiency, e.g. those with stimulated GH less than 3 µg/liter and IGF-I below the normal range.

Some caution should also be exercised when interpreting our results because nearly one third of the subjects did not complete the study, and the small number of subjects enrolled at each center may have increased the variability of the measures. Nonetheless, a critical analysis of the available data suggests to us that the management of the fully grown GH-deficient adolescent who completes his/her linear growth needs to be individualized. Retesting with potent secretagogues and stringent criteria for persistent GH deficiency need to be used (perhaps including low IGF-I concentrations) and the individual subject followed closely over several years. In those adolescents with normal BMD and satisfactory pattern of body composition, many can be safely followed without treatment and GH reinitiated later if the profile (i.e. decreased lean body mass, increased adiposity, and diminished BMD) warrants it. Because BMD continues to accrue for at least 18 months after discontinuation of GH treatment (36), it is likely that interrupting GH therapy for 2 yr in most subjects will still permit bone mass accrual, albeit at a lesser rate (7). This strategy may prove useful in terms of long-term compliance, because a convincing argument of need could then be better demonstrated to the patients.

In conclusion, 1) GH-deficient patients properly treated in childhood can have normal BMD, body composition, cardiac function, muscle strength, and measures of carbohydrate and lipid metabolism as well as measures of QOL at the time they reach adult height; and 2) continuation of GH therapy did not result in discernible benefits in these same measures compared with placebo-treated or control subjects during 2 yr of observation. Many GH-deficient adolescents who are in good metabolic status at the time of discontinuation of GH treatment may be able to discontinue GH for at least 2 yr. Careful follow-up should determine whether and when the adult GH deficiency syndrome develops and whether GH therapy is eventually warranted. If and when the phenotype of adult GH deficiency is fully identified, then the decision to resume GH therapy can be reconsidered; however, the time frame when this will develop may well depend on the individual patient, the severity of the GH deficiency, his/her level of fitness, or even antecedent GH doses. Hence, the treatment of the GH-deficient adolescent in transition should be individualized.


   Acknowledgments
 
Participating investigators and centers were Gertrude Costin, Children’s Hospital of Los Angeles, Los Angeles, CA; Paul DeLamater, Toledo, OH; Mitchell E. Geffner, University of California, Los Angeles, Children’s Hospital, Los Angeles, CA; John Germack and Robert Hoffman, Columbus, OH; Nancy Hopwood, University of Michigan Medical Center, Ann Arbor, MI; Campbell Howard, Children’s Mercy Hospital, Kansas City, MO; Gad Kettler, Children’s Hospital and Medical Center, Seattle, WA; Stephen H. LaFranchi, Oregon Health Sciences University, Portland, OR; Mary M. Lee, Massachusetts General Hospital, Boston, MA; Margaret MacGillvray, The Children’s Hospital of Buffalo, Buffalo, NY; Nelly Mauras, Nemours Children’s Clinic, Jacksonville, FL; Thomas Moshang, Childrens Hospital of Philadelphia, Philadelphia, PA; Ora H. Pescovitz, Indiana University, Indianapolis, IN; and Thomas A. Wilson, State University of New York at Stony Brook, Stony Brook, NY.

We are grateful to all the centers that participated in the study and to the principal investigators and study coordinators. We are also grateful to Dr. Timothy Wysocki for advice on the psychological data.


   Footnotes
 
This work was sponsored by Pharmacia Corp., a division of Pfizer, Inc.

First Published Online April 26, 2005

Abbreviations: ANCOVA, Analysis of covariance; BMD, bone mineral density; DEXA, dual-energy x-ray absorptiometry; E/A, early inflow/atrial inflow; GHD-DSQ, Growth Hormone Deficiency Disease-Specific Questionnaire; HDL, high-density lipoprotein; IGFBP, IGF-binding protein; ITT, insulin-induced hypoglycemia tolerance test; LV, left ventricular; QOL, quality of life; SAS-SR, Social Adjustment Scale Self Report Questionnaire.

1 Girls were given Premarin 0.625 mg daily and Provera 5 mg from d 15 to end of month (as separate medications or in Premphase formulation). Boys who complained of inadequate virilization or low libido were allowed to increase testosterone treatment to 200 mg twice monthly after the first year. Back

Received January 31, 2005.

Accepted April 20, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
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