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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 9 3115-3120
Copyright © 1998 by The Endocrine Society

Original Studies

Metabolic Consequences of 5-Year Growth Hormone (GH) Therapy in Children Treated with GH for Idiopathic Short Stature1

Paul Saenger, Kenneth M. Attie, Joan DiMartino-Nardi, Raymond Hintz, Lindley Frahm, James W. Frane and the Genentech Collaborative Study Group2

Department of Pediatrics, Division of Pediatric Endocrinology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York 10467; and Genentech, Inc., South San Francisco, California 94080

Address all correspondence and requests for reprints to: Paul Saenger, M.D., Division of Pediatric Endocrinology, Montefiore Medical Center, 111 East 210th Street, Bronx, New York 10467.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In a multicenter study the metabolic effects of 5 yr of GH therapy in children with idiopathic short stature were evaluated. Patients received 0.3 mg/kg·week recombinant human GH. Of the 121 patients who entered the study, data for 62 were analyzed at the final 5 yr point. Routine laboratory determinations were available for all 62 subjects at the 5 yr point. Special laboratory determinations, such as postprandial glucose and insulin, were available for only a subset of patients. Mean insulin-like growth factor I levels rose to 283 ± 101 µg/L, within the normal range using age-appropriate reference standards. T4, cholesterol, triglycerides, blood chemistries, and blood pressure showed no significant changes during the 5-yr period. Mean baseline and 2-h postprandial glucose levels remained unchanged. Both fasting and postprandial insulin levels rose substantively from low normal levels to the normal range (median, 4.9–43 mU/L). Mean hemoglobin A1c levels remained within the normal range throughout the study.

In summary, careful monitoring has not revealed any currently discernible metabolic side-effects of clinical significance after GH therapy in this 5-yr study of children with idiopathic short stature.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE SHORT-term auxological efficacy of human GH therapy in short, slowly growing children with normal GH responses to multiple provocative stimuli [idiopathic short stature (ISS)] has been studied by several investigators (1, 2, 3). To date, follow-up has been limited to 5 yr (4).

Therapy with recombinant GH commonly results in an increase in growth velocity to a variable degree (3, 5, 6), with a mean result of a doubling of the pretreatment growth rate in most studies during the first year of treatment (3, 5). Therapeutic efficacy tends to diminish thereafter, as seen in other populations treated with GH (7, 8). In a recent study (2), it was estimated that the predicted final height in some children without GH deficiency treated with pharmacological doses of GH increased by approximately 10 cm. The most recent analysis of the Genentech-sponsored trial (4), shows that GH treatment of patients with marked short stature (>=2 SD score) results in an increase in mean final height of 9.1 cm for boys (95% confidence limits, 5.4–12.8) and 5.6 cm for girls (95% confidence limits, 2.0–9.3) compared with untreated historial controls whose baseline height was below -2 SD score for age. However, these patients still do not achieve their midparent target height (4).

Although these clinical investigations focusing on auxological issues continue, concerns about the metabolic side-effects of GH treatment prompted our examination of the metabolic consequences of GH therapy for idiopathic short stature in a large multicenter trial. As we explore the widening indications for GH use in non-GH-deficient children (1, 9, 10, 11) and the clinical utility of varying GH doses in nonresponders (3), safety aspects in the context of metabolic side-effects need to be carefully investigated.

We studied the effects of 5 yr of GH treatment in children with ISS on levels of insulin-like growth factor I (IGF-I), L-T4, cholesterol, triglycerides, sodium, and potassium. We also measured effects on carbohydrate metabolism, as assessed by glucose and insulin levels in the fasting state and 120 min after a standard oral glucose load, as well as hemoglobin A1c levels.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
This multicenter study was conducted at 10 sites and was approved by the institutional review board at each center. The inclusion criteria for the study were age above 5 yr, height more than 1.9 SD below the mean for age (i.e. less than the third percentile), birth weight more than 2.5 kg, peak serum GH above 10 µg/L on at least one test, and bone age for girls of less than 9 yr and for boys of less than 10 yr. Weight was within the 10th to 90th percentile for height, and the growth rate was at the 50th percentile or below for age and sex for the 6-month period before enrollment. All subjects were prepubertal at the time of entry into the study (Table 1Go). Children receiving chronic drug therapy (e.g. methylphenidate or glucocorticoids) or with evidence of dysmorphic syndromes or systemic diseases were excluded (5, 6). Five year treatment data have been analyzed for this report.


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  		Table 1. Pretreatment characteristics of study patients

 
The study patients received 0.3 mg/kg·week recombinant human GH (Nutropin, somatropin, Genentech, South San Francisco, CA) either daily or three times per week (tiw) sc. The patients were initially randomized for the first year to either an observational control group or treatment with recombinant human GH (0.3 mg/kg total weekly dose, given tiw).

In subsequent years, the patients were randomized to receive 0.3 mg/kg·week recombinant human GH given either daily or tiw. Of the 121 patients who entered the study, a total of 80 achieved final or near-final height, as defined by a bone age of 16 yr or more in boys and of 14 yr or more in girls (4). Laboratory data were evaluated at 6-month intervals during GH treatment. Blood chemistry, liver function tests (serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, and bilirubin), serum T4, blood glucose, insulin, and hemoglobin A1c levels were measured at Smith-Kline Bioscience Laboratories (Van Nuys, CA). Hemoglobin A1c was determined using a chromotographic method (normal, <6.2%). IGF-I was measured using acid chromotography extraction (4, 12).

Glucose challenge was measured at 0 min in the fasting state and at 120 min after a standard glucose load consisting of 1.75 g glucose solution/kg, with a maximum of 75 g/dose. A standardized comparison of changes in biochemical parameters between baseline and treatment values was made using Student’s two-tailed t test. Results are expressed as the mean ± SD. P values < 0.05 were considered significant. For the 5-yr analyses, patients were included for each metabolic measure if data were available at 0 and 60 months. Because of skewing of data, statistical analyses were performed using median or log-transformed values for insulin and triglyceride measurements. Insulin values are shown as antilog in the figures to facilitate graphical depiction in units.

As daily vs. tiw GH treatment showed no difference in metabolic effects, only combined data for both groups are shown. The auxological difference in the two treatment groups has recently been reviewed (13).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
IGF-I

Mean IGF-I levels rose from baseline levels during treatment in both pubertal and prepubertal subjects (Table 2Go). Using age-appropriate standard reference levels, the data, expressed as the SD score for age and sex, are shown in Fig. 1.


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  		Table 2. Metabolic parameters and pubertal status at baseline and during 5-yr follow-up

 
T4

Mean T4 levels did not show any significant changes during the 5-yr follow-up period. There was a significant increase in T4 levels at 6 months in the group receiving daily GH. These changes were not accompanied by clinical symptoms and reverted to pretreatment levels by 12 months (Table 2Go).

Cholesterol and triglycerides

There were modest changes in mean total cholesterol and mean triglyceride concentrations during treatment that were not statistically or clinically significant (Table 2Go). At all times mean serum levels for both cholesterol and triglycerides remained in the normal range when applied to recently developed age-appropriate standards (14).

Na, K, and blood pressure

There were no significant changes in mean serum sodium or mean serum potassium during the 5 yr of treatment (Table 2Go). There was no change in mean blood pressure during the entire observation period.

Blood chemistries

Mean serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, and bilirubin levels showed no significant changes during the 5-yr period. Mean alkaline phosphatase rose in the treatment group (data not shown).

Carbohydrate tolerance and hemoglobin A1c

Mean baseline and 2 h postprandial glucose levels remained unchanged throughout the treatment period, whereas insulin showed a rise during treatment from low normal levels into the normal range (Table 2Go). After year 3 of the study, mean basal and postglucose load insulin levels showed no further rise (Fig. 2Go, a and b). The increases in mean postprandial insulin levels were 7-fold at 3 yr and 9-fold at 4 yr compared with control values. Follow-up of individual patients showed that no study subject became hyperinsulinemic in either the fasting or the postprandial state. Mean fasting and postprandial insulin levels remained within the normal range. Hemoglobin A1c levels (Fig. 3Go) remained stable in the normal range throughout the study. Glucose metabolism data were available for a smaller number of patients (see Table 2Go). There was, however, no statistically significant difference between the baseline characteristics of patients with or without glucose metabolism results. Thus, these results are representative of the general patient population.



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  		Figure 2. a and b, Fasting and postprandial insulin levels at baseline and during 5-yr follow-up. The hatched area denotes the normal range for the reference laboratory: 5–25 mU/mL at baseline and 16–166 mU/mL for postprandial levels.

 


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  		Figure 3. Hemoglogin A1c values at baseline and during 5-yr follow-up.

 
There were no correlations of basal and postglucose load insulin levels with body mass index or Tanner stage of puberty in either boys or girls (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Whereas GH prescribed for approved indications at approved dosages has been shown to be safe (15), long term studies of GH in ISS require continued vigilance to detect possible side-effects. In particular, the use of current doses of GH, which are higher than doses used in the past for classical GH deficiency, should increase our alertness for potential novel or unusual risks. It is noteworthy that adverse events associated with GH therapy, such as intracranial hypertension, slipped capital femoral epiphysis, pancreatitis, and gynecomastia, are generally not seen in patients with ISS (15). This study analyzes metabolic effects in a large and to date the longest study in children with ISS.

IGF-I

In response to GH administration, serum levels of IGF-I rise, as expected. The mean levels achieved remain within the normal range using age-appropriate standards. In response to GH administration, serum levels of IGF-I rose significantly. However, standardized scores returned to baseline levels by 48 months. IGF-I levels were less than those achieved in GH-deficient patients taking similar doses, possibly due to partial GH insensitivity in some ISS patients (16). IGF-I monitoring also may prove to be a useful tool to evaluate compliance with GH therapy.

T4

Administration of human GH to patients with GH deficiency has been reported to produce a variety of perturbations of thyroid function. A recent analysis of the effects of recombinant human GH on thyroid function showed that after 4 days of GH treatment (0.125 mg/m2·day), mean serum T4 levels decreased by 8%; in contrast, mean serum T3 levels increased by 21%. The increase in mean T3 levels led to a 54% decrease in mean TSH levels. These data are most consistent with enhanced extrathyroidal (including intrapituitary) conversion of T4 to T3 with a compensatory decrease in TSH secretion (17). In the same study an inconsequential short term rise in the T3/T4 ratio was seen that was reversed during prolonged treatment. In other long term studies, no significant changes in thyroid hormone levels were observed (18).

Five of the original patients in this study (6) were started on thyroid hormone replacement during the first 3 yr of the study. Their serum T4 levels ranged from 4.4–5.5 µg/dL at the time that thyroid replacement was initiated. The transient changes in thyroid hormone measurements seen with GH therapy are generally not associated with clinical disease.

Cholesterol/triglycerides

GH administration had a minimal effect on cholesterol and triglyceride levels when measured at annual intervals (14). In a study of normal individuals, GH administration decreased cholesterol levels after 1 week of very high doses, but not after 6 months using lesser amounts (19). In contrast, large doses of GH raised the triglyceride concentration, whereas 6 months of small doses had no effect (19).

The effects of exogenous GH on site-specific adipose tissue distribution (20) were not evaluated in our patients. Changes in adipose tissue distribution during GH therapy may be due to a GH-mediated decrease in insulin responsiveness that takes place in parallel to a decrease in the de novo triglyceride synthesis (20). Body mass index remained normal in the group of children evaluated here.

Fluid, electrolytes, and blood pressure

Mean sodium and potassium concentrations showed no significant change during the 5-yr course of study. Transient sodium and water retention after pituitary GH administration was described 30 yr ago (21). In acromegaly, both intra- and extracellular fluid volumes are increased. Studies of GH-deficient adults using recombinant human GH (22) yielded similar results. In 6 of 24 adults, fluid retention was apparent after 4 weeks of GH treatment, as evidenced by swelling of hands and feet. In a study that sought to determine whether 3 weeks of treatment with GH might facilitate the preservation of nitrogen and accelerate the loss of body fat during dietary restriction, the injection of GH resulted in cessation of weight loss for at least 1 week in 5 of 8 study subjects, and 5 subjects developed mild edema during the first treatment week. Not surprisingly, after GH was terminated, all subjects experienced a water diuresis (mean, 2.06 ± 1.25 kg). When higher doses of GH (10 mg/day for 7 days) were used in a study by Manson and Wilmore (24), water retention and edema formation became even more prevalent.

Fluid retention has been described in children with GH deficiency after both short and long term use of pituitary GH when using antipyrine kinetics as an indirect measure of total body water (25). Recent data by Ho et al. (26) show that the administration of hGH at a dose of 0.1 mg/kg·day for 5 days in adult volunteers acutely leads to an activation of the renin-angiotensin axis, which reached the maximum level 3–5 days after the first GH dose. Blood pressure did not change however. Although fluid retention commonly accompanies GH excess, it is unlikely that the chronic volume expansion seen in acromegaly arises solely from GH-induced activation of mineralocorticoid secretion. It is well known that escape from sodium retention occurs promptly after protracted aldosterone elevation (26). In a recent study assessing the 1-yr effects of GH on blood pressure, atrial natriuretic factor, aldosterone, and PRA, no changes compatible with sodium retention were seen (27). The relationship between transient sodium retention and pseudotumor cerebri accompanying GH administration remains to be explored (15).

Carbohydrate tolerance and hemoglobin A1c

In hypopituitary children, GH treatment has been associated with normalization of glucose turnover and insulin secretion and has led to either unchanged or increased insulin responses to oral glucose administration (28, 29, 30). Hindmarsh et al. (31) measured glycemic responses to GH therapy in short normal children. Fasting serum insulin concentrations increased from 5.4 ± 3.5 to 15.3 ± 8.7 mU/L at the end of the first year of treatment, which is very similar to our findings.

Fasting levels decreased slightly during the second year. No postprandial insulin levels were reported by these investigators. They conclude that tolerance to the effects of GH on carbohydrate metabolism occurs (31). In children with ISS, Lesage et al. (2) observed nearly complete reversal of hyperinsulinism within 12 months of discontinuation of GH therapy in their group of 10 prepubertal children treated with 2–3 times the dose of recombinant GH used here. Similarly, in a group of Turner syndrome patients we recently showed a progressive normalization of insulin levels after GH treatment was discontinued (32).

The rise in insulin levels shown here is substantive, although levels remain within the normal range for postprandial insulin levels as defined by the reference laboratory we used. The clinical significance, if any, of these changes is unclear. Follow-up of patients without GH deficiency treated for a similar time period with comparable doses of GH shows a decline in postprandial insulin levels after GH therapy is discontinued (32). These data, therefore, do not support the concept that GH therapy of this duration will lead to ß-cell exhaustion.

Heptulla et al. (33) recently reported that the effects of GH on insulin sensitivity in prepubertal children with ISS anticipate the changes in carbohydrate tolerance seen typically during normal adolescence. GH treatment in ISS may lead to a prolongation of the physiological state of insulin resistance seen in normal puberty (34, 35). The long term implications of prolonged insulin resistance are not known. It is reassuring, however, that despite uninterrupted GH treatment, the insulin levels when measured fasting and 2 h after a standard glucose load showed no further rise after the first 3 yr of GH therapy. More detailed analysis of the insulin resistance associated with puberty using euglycemic and hyperglycemic clamp techniques (34, 35) suggests that GH-induced insulin resistance spares hepatic action of insulin and is limited to peripheral glucose metabolism. The insulin resistance is thus associated with a greater fall in branched chain and other essential amino acids. The hyperinsulinemia seen in puberty or during GH therapy may, therefore, amplify the anabolic effects of insulin on protein metabolism in puberty (33, 34).

It is currently not known whether the metabolic effects of GH are dependent on the mean serum value of GH over a given time period, the total GH circulating in plasma during that period (area under the curve), the number and/or amplitude of GH peaks achieved, or the maximum GH levels achieved. Using the dosage schedule described in this study, peak GH levels as high as 32 ng/mL have been measured after sc injections (36). This order of magnitude of GH levels is seen in 24-h studies of GH dynamics in normal healthy control children (37). In addition, IGF-I concentrations or the concentration of IGF-binding proteins may modulate the metabolic effects of GH (38).

In summary, careful monitoring has not revealed any currently discernible metabolic side-effects of clinical significance during this long term study of GH therapy in children with ISS. In particular, insulin levels increase but remain within the normal range, as do glucose and hemoglobin A1c. Although GH treatment in this group of children appears to be safe, continued surveillance is necessary.



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  		Figure 1. Mean (±SD) IGF-I ± SD score in treated (5 yr) and control (1 yr) patients.

 

   Footnotes
 
1 Presented in part at the Annual Meeting of the American Pediatric Society and the Society for Pediatric Research, San Diego, CA, May 1995. Back

2 The Genentech Collaborative Study Group is composed of: A. J. Johanson (Genentech, South San Francisco, CA), J. Baptista (Genentech), J. Kuntze (Genentech), R. Blizzard (University of Virgina, Charlottesville, VA), J. Cara (Wright State University, Detroit, MI), S. Chernausek (Children’s Hospital, Cincinnati, OH), M. Geffner (University of California-Los Angeles Medical Center), J. Gertner (Cornell Medical Center, New York, NY), N. Hopwood (University of Michigan, Ann Arbor, MI), S. Kaplan (University of California-San Francisco Medical Center), B. Lippe, University of California Los Angeles Medical Center), L. Plotnick (Johns Hopkins Hospital, Baltimore, MD), and A. Rogol (University of Virginia, Charlottesville, VA). Back

Received December 5, 1997.

Revised April 10, 1998.

Accepted May 22, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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