0021-972X/00/$03.00/0 The Journal of Clinical Endocrinology & Metabolism Copyright © 2000 by The Endocrine Society
Vol. 85, No. 5 Printed in U.S.A.
Continuation of Growth Hormone (GH) Therapy in GH-Deficient Patients during Transition from Childhood to Adulthood: Impact on Insulin Sensitivity and Substrate Metabolism HELENE NØRRELUND, NINA VAHL, ANDERS JUUL, NIELS MØLLER, K. G. M. M. ALBERTI, NIELS E. SKAKKEBÆK, JENS SANDAHL CHRISTIANSEN, AND JENS OTTO LUNDE JØRGENSEN Medical Department M (Endocrinology and Diabetes) (H.N., N.V., N.M., J.S.C., J.O.L.J.), Aarhus University Hospital, DK-8000 C, Aarhus, Denmark; Department of Growth and Reproduction (A.J., N.E.S.), Copenhagen University Hospital, DK-2100 Copenhagen, Denmark; and Department of Metabolic Medicine (K.G.M.M.A.), University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH United Kingdom ABSTRACT The appropriate management of GH-deficient patients during transition from childhood to adulthood has not been reported in controlled trials, even though there is evidence to suggest that this phase is associated with specific problems in relation to GH sensitivity. An issue of particular interest is the impact of GH substitution on insulin sensitivity, which normally declines during puberty. We, therefore, evaluated insulin sensitivity (euglycemic glucose clamp) and substrate metabolism in 18 GH-deficient patients (6 females and 12 males; age, 20 ⫾ 1 yr; body mass index, 25 ⫾ 1 kg/m2) in a placebo-controlled, parallel study. Measurements were made at baseline, where all patients were on their regular GH replacement, after 12 months of either continued GH (0.018 ⫾ 0.001 mg/kg䡠day) or placebo, and finally after 12 months of open phase GH therapy (0.016 mg/kg䡠day). Before study entry GH deficiency was reconfirmed by a stimulation test. During the double-blind phase, insulin sensitivity and fat mass tended to increase in the placebo group [⌬M-value
A
DULTS WITH GH deficiency have increased body fat mass (TBF) and decreased fat-free mass (FFM) (1, 2), which together may impair insulin sensitivity and cause adverse metabolic effects. Replacement therapy with recombinant GH tends to normalize body composition (3, 4), but GH also possesses direct insulin antagonistic effects (5, 6). Indeed, previous studies (3, 7–9) of GH replacement therapy in hypopituitary adults have shown an increase in fasting plasma glucose, insulin, and C-peptide levels, suggesting development of insulin resistance during GH treatment. Euglycemic clamp studies in GH-deficient adults have demonstrated a significant decrease in M-value (glucose infusion rate) after 6 weeks of treatment (10), followed by a significant increase after 6 months of treatment, however, not reaching baseline values. Although this and other studies (11) indicate that the direct insulin antagonistic actions of GH may be balanced by the long-term beneficial effects on body com-
Received September 15, 1999. Revision received January 14, 2000. Accepted February 2, 2000. Address correspondence and requests for reprints to: Helene Nørrelund, Medical Department M, Aarhus Kommunehospital, DK-8000 C, Aarhus, Denmark. E-mail:
[email protected].
(mg/kg䡠min), ⫺0.7 ⫾ 1.1 (GH) vs. 1.3 ⫾ 0.8 (placebo), P ⫽ 0.18; ⌬TBF (kg), 0.9 ⫾ 1.2 (GH) vs. 4.4 ⫾ 1.6 (placebo), P ⫽ 0.1]. Rates of lipid oxidation decreased [⌬lipid oxidation (mg/kg䡠min), 0.02 ⫾ 0.14 (GH) vs. ⫺0.32 ⫾ 0.13 (placebo), P ⬍ 0.05], whereas glucose oxidation increased in the placebo-treated group (P ⬍ 0.05). In the open phase, a decrease in insulin sensitivity was found in the former placebo group, although they lost body fat and increased fat-free mass [Mvalue (mg/kg䡠min), 5.1 ⫾ 0.7 (placebo) vs. 3.4 ⫾ 1.0 (open), P ⫽ 0.09]. In the group randomized to continued GH treatment almost all hormonal and metabolic parameters remained unchanged during the study. In conclusion, 1) discontinuation of GH therapy for 1 yr in adolescent patients induces fat accumulation without compromising insulin sensitivity; and 2) the beneficial effects of continued GH treatment on body composition in terms of decrease in fat mass and increase in fat-free mass does not fully balance the direct insulin antagonistic effects. (J Clin Endocrinol Metab 85: 1912–1917, 2000)
position and physical fitness, the overall effects of GH substitution on insulin sensitivity remain unresolved. The appropriate management of GH-deficient patients during transition from childhood to adulthood has not been investigated in controlled trials, but there is evidence to suggest that this particular phase may be associated with specific problems in relation to GH sensitivity (12–15). An issue of particular interest is the impact of GH substitution on insulin sensitivity, which usually declines during normal puberty (16 –18). To pursue this, we conducted a trial in a group of GH-treated young adults with childhood-onset disease. At the time where discontinuation of GH therapy traditionally would be considered, the patients were randomized to either continued GH or placebo for 1 yr, followed by a 2nd yr of open GH treatment. Substrate metabolism and insulin sensitivity were studied at baseline, after 12 months of either continued GH or placebo, and finally after 12 months of open phase GH therapy. Subjects and Methods Subjects Eighteen subjects (6 females and 12 males; age, 20 ⫾ 1 yr; body mass index, 25 ⫾ 1 kg/m2) with childhood-onset GH deficiency (GHD) re-
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GH THERAPY IN GH-DEFICIENT PATIENTS confirmed by at least one classical GH stimulation test were included in the study. All participants were retested and had a subnormal GH response to infusion of arginine [peak GH response (g/L): 1.2 ⫾ 0.5]. The etiology of GHD was idiopathic in 12 patients. A detailed description of each patient is given in Table 1. All 18 subjects completed the double-blind phase. Two subjects withdrew after 21 months; one because of regrowth of an intracranial tumor, and one because of compliance problems. Both of these patients had received GH since the start of the study. The study was approved by the regional Ethical Committee and the National Board of Health and was conducted according to the Declaration of Helsinki and the guidelines of Good Clinical Practice.
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glycemia (M-value) from the isotopically determined overall appearance rate for glucose. Indirect calorimetry was performed using a ventilated hood system (Deltatrac; Datex Instrumentarium, Helsinki, Finland) before the start and at end of insulin infusion to assess resting energy expenditure (EE) and respiratory exchange ratio (RQ). Net lipid and glucose oxidation rates [Rd(ox)] were calculated from the above measurements, and protein oxidation rates were estimated from the urinary excretion of urea (19). Net nonoxidative glucose disposal [Rd(non-ox)] was calculated by subtracting oxidative glucose disposal [Rd(ox)] from total glucose disposal (Rd) measured isotopically.
Hormone and substrate analyses
Study protocol During the first 12 months, the study had a randomized, parallel, double-blind, placebo-controlled design. The subsequent 12 months was an open phase, during which all patients received GH. In the doubleblind phase the patients continued their usual GH dose (0.018 ⫾ 0.001 mg/kg䡠day; Norditropin, Novo Nordisk A/S, Copenhagen, Denmark). Nine subjects received GH, and nine received placebo. In the open phase, the dose was escalated starting with 0.004 mg/kg䡠day in the first 2 weeks, 0.008 mg/kg䡠day in weeks 3– 6, and 0.016 mg/kg䡠day from week 7 onward. No adverse advents were recorded. There was no washout period before either treatment was started. The patients were admitted to the hospital for 2 days at baseline, 12 months, and 24 months. In addition, all patients were seen at the outpatient clinic every 3 months for interviews and physical examination.
Body composition and euglycemic hyperinsulinemic glucose clamp TBF and FFM were measured by dual-energy x-ray absorptiometry using a Hologic QDR-2000 densitometer (Hologic, Inc., Waltham, MA). After an overnight fast, a bolus of 20 Ci [3-3H]-glucose (New England, Nuclear, Boston, MA) was given, followed by a continous infusion of 0.2 Ci/min for 5 h. Two and one half hours were allowed for the isotope to equilibrate. Insulin sensitivity was estimated by means of a hyperinsulinemic euglycemic clamp. From 1030 –1300 h a constant amount (0.6 mU/ kg䡠min) of insulin (Actrapid; Novo Nordisk) was infused; based on measurements every 5 min, plasma glucose was clamped at 5.0 mmol/L by infusion of variable rates of a 20% glucose solution. Plasma glucose was measured on a glucose analyzer (Beckman Coulter, Inc., Palo Alto, CA) immediately after sampling. Blood samples were drawn at baseline and in triplicate the last 30 min of both the 2.5-h basal period and the 2.5-h clamp period. During the clamp, hepatic glucose production was calculated by subtracting the amount of exogenous glucose necessary to maintain euTABLE 1. Clinical characteristics of the patients included in the study Patient no.
Age
Sex
Etiology
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
18 22 20 19 17 16 20 18 19 16 19 18 21 19 22 26 23 25
F F F F F F M M M M M M M M M M M M
Craniopharyngeoma Idiopathic Idiopathic Medulloblastoma Germinoma Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Cerebral tumor Idiopathic Idiopathic Idiopathic Astrocytoma Cerebral tumor Idiopathic
Substitution therapy
T,A,G,D T,G T,A,G,D T,G T,A,D T,A T T
A double monoclonal immunofluometric assay (Wallac, Inc., Turku, Finland) was used to measure serum GH. Serum insulin-like growth factor (IGF) I was measured by a noncompetitive time-resolved immunofluometric assay after removal of IGF-binding proteins with acid ethanol. Insulin was measured by a conventional in-house RIA. Nonesterified fatty acids (NEFAs) were determined by a colorimetric method using a commercial kit (Wako Chemicals, Neuss, Germany). Whole blood glycerol, 3-hydroxybutyrate, alanine, and lactate were analyzed by autofluorimetric enzymatic methods (20). Glucose turnover was estimated according to the non-steady-state model of Steele et al. as modified by De Bodo et al. (21) based on data from the infused tritiated glucose tracer.
Statistical analyses Data, given as mean ⫾ sem, are based on triplicate measurements within the last 30 min of the basal and clamp period. Baseline data in the two treatment groups were compared with Student’s t test for unpaired data. In each group, the effect of continuation or discontinuation was evaluated by a paired t test. Analysis of treatment effect was performed by comparing ⌬ values in the GH vs. placebo group by Student’s t test for unpaired data. Resting metabolic rate data were normalized for differences in FFM and TBF by analysis of covariance, which allows for the removal of the linear effect of the covariate without making the assumption of a zero intercept. Analyses were made on log-transformed data when not normally distributed, as tested by Kolmogorov-Smirnov. A P value below 0.05 was considered significant. All statistical computations were performed with SPSS for Windows version 8.0 (SPSS, Inc., Chicago, IL).
Results Baseline data
At baseline levels of GH and IGF-I were similar [GH (g/L), 1.6 ⫾ 0.3 (GH) vs. 1.1 ⫾ 0.1 (placebo), P ⬎ 0.05; IGF-I (g/L), 340 ⫾ 57 (GH) vs. 422 ⫾ 57 (placebo), P ⬎ 0.05] (Fig. 1). The placebo group had more body fat [TBF (kg), 16 ⫾ 2 (GH) vs. 23 ⫾ 2 (placebo), P ⬍ 0.05] (Table 2), and increased plasma concentration of insulin [insulin (pmol/L), 34 ⫾ 4 (GH) vs. 75 ⫾ 10 (placebo), P ⬍ 0.01] and glucose [glucose (mmol/L), 4.8 ⫾ 0.1 (GH) vs. 5.1 ⫾ 0.1 (placebo), P ⬍ 0.01] (Fig. 1). During the clamp, comparable glucose infusion rates (M-value) were found [M-value (mg/kg body weight䡠min), 4.8 ⫾ 1.0 (GH) vs. 3.8 ⫾ 0.6 (placebo), P ⬎ 0.05] (Table 2), and no differences in EE, urea excretion, RQ, substrate oxidation, or hepatic glucose production were recorded.
T
12 months
T,A,G,D T,A T,A,G,D T,A,G,D T,A,G,D T,G
During the double-blind phase, insulin sensitivity increased among placebo-treated patients (P ⬍ 0.05) (Fig. 2). The comparison of change in M-value between GH-treated and placebo-treated patients failed to reach significance [⌬M-value (mg/kg䡠min), ⫺0.7 ⫾ 1.1 (GH) vs. 1.3 ⫾ 0.8 (placebo), P ⫽ 0.18] (Table 2). TBF tended to increase in the placebo group [⌬TBF (kg), 0.9 ⫾ 1.2 (GH) vs. 4.4 ⫾ 1.6
T, Thyroid replacement; G, gonadal steroid replacement; D, dDAVP; A, adrenal replacement.
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FIG. 1. Mean ⫾ SEM serum concentration of GH, IGF-I, insulin, and plasma glucose in the basal postabsorptive state. ^, Baseline data compared with Student’s t test for unpaired data (P ⬍ 0.01); -p-, dGH vs. dPlacebo (unpaired t test); *, the effect of GH evaluated by a paired t test (12 months vs. 24 months; P ⬍ 0.01); f, GH/GH; 䡺, placebo/GH.
(placebo), P ⫽ 0.1] (Fig. 2), whereas rates of lipid oxidation decreased (P ⬍ 0.05) (Fig. 3). Circulating levels of insulin decreased in the placebo group [⌬insulin (pmol/L), 13 ⫾ 11 (GH) vs. ⫺32 ⫾ 7 (placebo), P ⬍ 0.01] (Fig. 1). The plasma level of alanine increased among placebo-treated patients [⌬alanine (mol/L), ⫺28 ⫾ 10 (GH) vs. 57 ⫾ 11 (placebo), P ⬍ 0.01], whereas changes were comparable with regard to lactate, glycerol, NEFA, and hydroxybutyrate (Table 2).
EE tended to decrease among placebo-treated patients [⌬EE (kcal/24 h), 18 ⫾ 72 (GH) vs. ⫺134 ⫾ 73 (placebo), P ⫽ 0.1], whereas the RQ increased [⌬RQ, ⫺0.01 ⫾ 0.02 (GH) vs. 0.05 ⫾ 0.02 (placebo), P ⬍ 0.05] (Table 2). Glucose oxidation increased in the placebo group [⌬glucose oxidation (mg/ kg䡠min), ⫺0.2 ⫾ 0.2 (GH) vs. 0.3 ⫾ 0.2 (placebo), P ⬍ 0.05] (Fig. 3), but neither total nor nonoxidative glucose turnover differed between the groups. Comparable differences were recorded during the clamp, where the change in hepatic
GH THERAPY IN GH-DEFICIENT PATIENTS
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TABLE 2. Body composition measurements by dual-energy x-ray absorptiometry, plasma concentration of substrate, EE, and the RQ in the basal postabsorptive state and M-value at the end of a euglycemic clamp (mean ⫾ SEM) 0 months
TBF (kg) FFM (kg) Alanine (mol/L) Lactate (mol/L) 3-Hydroxy-butyrate (mol/L) Nonesterified fatty acids (mol/L) Glycerol (mol/L) EE (kcal/24 h) RQ M-value (mg/kg·min)
12 months
24 months
GH
Placebo
Pa
GH
Placebo
Pb
GH
Placebo
16 ⫾ 2 49 ⫾ 3 221 ⫾ 11 576 ⫾ 34 149 ⫾ 30 0.8 ⫾ 0.1 43 ⫾ 2 1520 ⫾ 91 0.83 ⫾ 0.02 4.8 ⫾ 1.0
23 ⫾ 2 50 ⫾ 6 181 ⫾ 11 543 ⫾ 30 88 ⫾ 15 0.64 ⫾ 0.04 35 ⫾ 2 1681 ⫾ 112 0.83 ⫾ 0.01 3.8 ⫾ 0.6
c
17 ⫾ 2 51 ⫾ 3 193 ⫾ 8 556 ⫾ 51 122 ⫾ 17 0.6 ⫾ 0.1 44 ⫾ 2 1538 ⫾ 99 0.82 ⫾ 0.02 4.1 ⫾ 0.7
27 ⫾ 3 51 ⫾ 5 239 ⫾ 9 582 ⫾ 40 26 ⫾ 5 0.44 ⫾ 0.03 36 ⫾ 5 1547 ⫾ 106 0.87 ⫾ 0.01 5.1 ⫾ 0.7
0.1
15 ⫾ 2 52 ⫾ 4 255 ⫾ 17d 601 ⫾ 52 115 ⫾ 34 0.7 ⫾ 0.1 48 ⫾ 5 1443 ⫾ 99 0.84 ⫾ 0.02 3.6 ⫾ 0.7
20 ⫾ 3d 58 ⫾ 6d 261 ⫾ 18 746 ⫾ 85 84 ⫾ 18d 0.6 ⫾ 0.1d 39 ⫾ 4d 1704 ⫾ 119 0.84 ⫾ 0.01d 3.4 ⫾ 1.0
e
c
e
0.1 c
0.18
a
Baseline data was compared with Student’s t test for unpaired data. b Analysis of treatment effect was performed by comparing delta values in the GH vs. placebo group by Student’s t test for unpaired data. c P ⬍ 0.05. d In each group, the effect of GH was evaluated by a paired t test (12 months vs. 24 months). Indicates that values differ significantly. e P ⬍ 0.01.
glucose production failed to reach statistical significance [⌬HGP (mg/kg䡠min), ⫺0.03 ⫾ 0.19 (GH) vs. ⫺0.21 ⫾ 0.13 (placebo), P ⫽ 0.5]. 24 months
In the open phase, the M-value tended to decrease [Mvalue (mg/kg䡠min), 5.1 ⫾ 0.7 (12 months) vs. 3.4 ⫾ 1.0 (24 months), P ⫽ 0.09] in the former placebo group (Fig. 2). A significant decrease in TBF was found [TBF (kg), 27 ⫾ 3 (12 months) vs. 20 ⫾ 3 (24 months), P ⬍ 0.05] (Fig. 2), together with an increase in FFM [FFM (kg), 51 ⫾ 5 (12 months) vs. 58 ⫾ 6 (24 months), P ⬍ 0.05] (Table 2). No changes in body composition were recorded in the group randomized to continued GH treatment. Circulating levels of insulin increased [insulin (pmol/L), 44 ⫾ 5 (12 months) vs. 110 ⫾ 30 (24 months), P ⬍ 0.05] in the previous placebo group (Fig. 1), together with increased concentrations of glycerol, NEFA, and 3-hydroxybutyrate (P ⬍ 0.01), whereas an increase in alanine level was found among GH-treated patients (P ⬍ 0.01) (Table 2). The RQ decreased in the former placebo group [RQ, 0.87 ⫾ 0.01 (12 months) vs. 0.84 ⫾ 0.01 (24 months), P ⬍ 0.05 ], and lipid oxidation increased [lipid oxidation (kcal/24 h), 491 ⫾ 98 (12 months) vs. 695 ⫾ 82 (24 months), P ⫽ 0.1] (Fig. 3). Glucose oxidation tended to decrease (P ⫽ 0.14), whereas total glucose turnover remained unchanged. Discussion
The aim of the present study was to investigate the effect of discontinued GH replacement therapy on insulin sensitivity and substrate metabolism in GH-deficient adolescents in relation to concomitant changes in body composition. The study demonstrates that discontinuation of GH in transition phase patients is associated with an increase in TBF in parallel with increased insulin sensitivity. Resumption of GH treatment is associated with a decrease in insulin sensitivity despite a concomitant reduction in fat mass and increase in FFM. The study clearly suggests that in this particular patient group the direct insulin antagonistic actions of GH dominate over the effects on body composition with regard to the net
effect on insulin sensitivity. By coincidence, our placebo group was more obese and hyperinsulinemic at baseline. Insulin sensitivity becomes diminished during normal puberty (16, 18). Fasting plasma insulin and C-peptide concentrations were higher in adolescents than in preadolescents and adults, and despite identical glucose increments during a hyperglycemic clamp, both first- and second-phase plasma insulin and C-peptide responses were markedly greater (16). A positive correlation between GH response to arginine and -cell response to glucose has also been demonstrated, suggesting that insulin resistance during normal puberty may be causally linked to the concomitant increase in GH secretion (17). Our study confirms and extends this notion. As shown previously, similarities between the so-called metabolic syndrome and untreated GHD in adults include premature atherosclerosis, visceral obesity, dyslipidemia, increased prevalence of hypertension, and insulin resistance (22–25). The change in atherogenic risk factors has also been studied in GH-deficient children treated with GH for 1 yr (26). A decrease in body fat, as well as an increase in FFM, was demonstrated. This improvement in body composition during GH treatment suggests beneficial effects of GH on body composition, which may reduce the risk of developing premature atherosclerosis. The beneficial effect of GH on body composition has also been demonstrated by discontinuation of GH therapy in young GH-deficient adults, which resulted in a significant decrease in both muscle bulk and strength after 6 –12 months (27). In the present study, a decrease in lipid oxidation and increase in glucose oxidation was observed with GH discontinuation. This is in line with earlier observations (28, 29), as GH seems to exert little effect on total glucose turnover and utilization, whereas lipid mobilization partitions glucose flux into nonoxidative pathways. GH treatment causes insulin antagonism. In patients with intact -cell function these changes are counterbalanced by hyperinsulinemia, which, by some, is considered a cardiovascular risk factor (23). Continuous GH infusions induce acute insulin resistance characterized by impaired suppression of hepatic glucose production and decreased insulindependent glucose disposal (5, 30 –32). An inhibition of in-
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FIG. 2. Change in M-value and TBF.
sulin-mediated activation of the glycogen synthase in skeletal muscle biopsies by a mechanism distal to insulin receptor binding and kinase activity has been demonstrated (32, 33), whereas insulin receptor concentration and affinity seem unchanged (5, 30, 35). The increased lipid oxidation could also be of importance for the insulin-resistance seen, since it may lead to a decreased glucose use due to the “glucose-NEFA cycle” (36). Several lines of evidence support the notion that GH stimulates EE (3, 37–39). In the present study, EE decreased with GH discontinuation. It has been suggested that the calorigenic actions of GH are, in part, secondary to the increments in FFM. In the present study, no decrease in FFM was observed in the placebo-treated group. Furthermore, stimulation of EE has been recorded after only 5 h of iv GH infusion in normal subjects (33), implying that GH may stimulate EE independent of body composition.
FIG. 3. Lipid oxidation, disposal rate, and oxidation of glucose in the basal postabsorptive state (mean ⫾ SEM). -p-, dGH vs. dPlacebo (unpaired t test); f, GH/GH; 䡺, placebo/GH.
GH THERAPY IN GH-DEFICIENT PATIENTS
In conclusion, our data indicate that during adolescence the beneficial effects on body composition of continued GH substitution in GH-deficient patients do not overcome the direct insulin antagonistic effects of GH. Whether the GHinduced relative insulin resistance observed in these patients is unfavorable is uncertain, inasmuch as normal puberty is associated with reduced insulin sensitivity. Still, the possibility of reducing the GH dose after completion of puberty merits consideration. At any rate, this study implies that the medical care of transition phase patients in terms of GH substitution remains a difficult challenge and should involve multidisciplinary collaboration. References 1. Rosen T, Bosaeus I, Tolli J, Lindstedt G, Bengtsson BA. 1993 Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency. Clin Endocrinol (Oxf.). 38:63–71. 2. Collip PJ, Curti V, Thomason M. 1973 Body composition changes in children receiving growth hormone. Metabolism. 22:589 –595. 3. Salomon F, Cuneo RC, Hesp R, Sonksen PH. 1989 The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med. 321:1797–1803. 4. Jorgensen JO, Pedersen SA, Thuesen L, et al. 1989 Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet. 1:1221–1225. 5. Bratusch-Marrain PR, Smith D, DeFronzo RA. 1982 The effect of growth hormone on glucose metabolism and insulin secretion in man. J Clin Endocrinol Metab. 55:973–982. 6. Sherwin RS, Schulman GA, Hendler RG. 1983 Effect of growth hormone on oral glucose tolerance and circulating metabolic fuels in man. Diabetologia. 24:155–161. 7. Binnerts A, Swart GR, Wilson JH, et al. 1992 The effect of growth hormone administration in growth hormone deficient adults on bone, protein, carbohydrate and lipid homeostasis, as well as on body composition. Clin Endocrinol (Oxf.). 37:79 – 87. 8. Degerblad M, Elgindy N, Hall K, Sjoberg HE, Thoren M. 1992 Potent effect of recombinant growth hormone on bone mineral density and body composition in adults with panhypopituitarism. Acta Endocrinol Copenh. 126:387–393. 9. Rosen T, Johannsson G, Hallgren P, Caidahl K, Bosaeus I, Bengtsson BA. 1994 Beneficial effects of 12 months replacement therapy with recombinant human growth hormone to growth hormone deficient adults. Endocrinol Metab. 1:55– 66. 10. Fowelin J, Attvall S, Lager I, Bengtsson BA. 1993 Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. Metabolism. 42:1443–1447. 11. Verhelst J, Abs R, Vandeweghe M, et al. 1997 Two years of replacement therapy in adults with growth hormone deficiency. Clin Endocrinol (Oxf.). 47:485– 494. 12. Brook CG, Hindmarsh PC, Stanhope R. 1988 Growth and growth hormone secretion. J Endocrinol. 119:179 –184. 13. Loche S, Casini MR, Faedda A. 1996 The GH/IGF-I axis in puberty. Br J Clin Pract Suppl. 85:1– 4. 14. Tanner JM. 1987 Issues and advances in adolescent growth and development. J Adolesc Health Care. 8:470 – 478. 15. Price DA, Shalet SM, Clayton PE. 1988 Management of idiopathic growth hormone deficient patients during puberty. Acta Paediatr Scand Suppl. 347:44 –51. 16. Caprio S, Plewe G, Diamond MP, et al. 1989 Increased insulin secretion in puberty: a compensatory response to reductions in insulin sensitivity. J Pediatr. 114:963–967. 17. Benassi L, Tridenti G, Orlandi N, Pezzarossa A. 1991 Glucose tolerance and insulin release in adolescent female. J Endocrinol Invest. 14:751–756.
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