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Original Studies |
Hôpital Robert Debré (G.T., M.N.), Paris, France 75019; Hôpital Necker-Enfants Malades (A.M.P.), Paris, France; Hôpital Cochin (J.C.R.), Paris, France
Address all correspondence and requests for reprints to: Dr. Guy Touati, Centre d’Investigation Clinique, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France.
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Abstract |
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Baseline GH secretion, GH binding protein (BP), insulin-like growth factor-I (IGF-I), and IGFBP3 levels were at the lower limit of normal. The rhGH treatment increased IGF-I and IGFBP3 plasma levels to above-normal values. All patients showed an increase in GV, and mean GV increased from 1.9–5.4 cm/yr (P < 0.001). Compared with the value on day 0, lean body mass increased by 12.2% (P < 0.01), and the fat mass excess fell by 19.5% (P < 0.01). Decreased glucose tolerance (as determined by oral glucose tolerance test) and increased glycosylated hemoglobin levels were observed during treatment. This effect may be attributed to insulin resistance, as reflected by induced hyperinsulinemia.
Eleven children were monitored for 1 yr after the cessation of GH therapy. GV fell to pretreatment values, whereas height in SD score at the end of the 2nd yr was lower (P < 0.01) than before treatment. Weight and fat mass again increased markedly. Although long-term controlled studies are needed to assess the risks and benefits of GH therapy in this setting, our results suggest that rhGH may partially counteract the adverse effects of glucocorticoids on growth and metabolism in patients with chronic inflammatory disease.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We assessed the effects of a 1-yr course of recombinant human GH (rhGH) on growth and body composition in 14 children with JCA and considerably impaired growth.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Inclusion criteria were age >3 yr, prepubertal status, bone age <12 yr for boys and <10 yr for girls, height <-2 SD score for chronological age (CA), GV <-1 SD score for CA during the year preceding inclusion, and GC treatment for more than 2 yr with a stable dose for more than 6 months before inclusion. Exclusion criteria were endocrinopathy, renal failure, nephrotic syndrome, diabetes, heart failure, liver failure, and previous GH treatment.
Description of patients
Fifteen prepubertal children with severe systemic and/or
polyarticular JCA and growth retardation were enrolled. A 7-yr-old
child withdrew after 6 months of rhGH treatment because he disliked the
frequent subcutaneous injections and was excluded from the analysis.
Fourteen children completed 1 yr of rhGH treatment (Table 1
). Mean age at the onset of arthritis
was 3 yr and 4 months, and mean age at the outset of steroid therapy
was 3 yr and 9 months. The disease began before 5 yr of age in 12 of
the 14 children. Mean age at the outset of rhGH treatment was 9 yr and
8 months (range, 6 yr and 2 months to 14 yr and 4 months). All were
receiving prednisone. Two patients received GC on alternate days,
whereas 12 received it every day. Despite a mean daily prednisone dose
of 0.38 mg/kg per day, the inflammatory process persisted, because the
mean erythrocyte sedimentation rate (ESR) at enrollment was 58 mm at
1 h (range, 12–102 mm). All the patients had restricted activity
because of pain and limited joint mobility.
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Patients received rhGH (Genotonorm, Pharmacia SA) at a dose of 1.4 U/kg per week, (4.2 mg/kg per week) given in a daily subcutaneous injection. Patients received rhGH for 1 yr and were monitored for a 2nd yr off treatment. They were seen by the same investigator at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months after enrollment. At each visit, three consecutive measurements of standing height were made with a Harpenden stadiometer and were averaged. Height, weight, and GV were compared with reference values for the French population (6a). Puberty was graded with Tanner scores by the same experienced endocrinologist. Joint involvement was assessed clinically by the same experienced rheumatologist. Skeletal age was assessed every 6 months according to the Greulich-Pyle method on radiographs of the left hand. Dietary intakes were calculated from mean values of a 3-day assessment before and after 6 and 12 months of rhGH treatment.
The blood cell count, ESR, albuminemia, plasma amino acids, fasting glycemia, glycosylated hemoglobin (HbA1c), insulin-like growth factor-I (IGF-I), and IGF binding protein-3 (IGFBP-3), were measured at baseline and after 1, 6, 12, and 24 months. An oral glucose tolerance test (OGTT) was performed at the same times.
Methods
Body composition was measured by means of dual-energy X-ray absorptiometry (DEXA) (Hologic QDR1000W/892 mef 1990, Hologic, Boston, MA) as described by Haarbo et al. (7).
GH serum concentrations were measured by RIA (Elsa hGH, Cis Bio International, Giff sur Yvette, France). GH secretion was evaluated by means of the glucagon-betaxolol stimulation test, and spontaneous nocturnal secretion was determined by sampling every 20 min. The area under the curve during an 8-h sleep was integrated, and values were calculated. GHBP, IGF-I, and IGFBP-3 levels were measured in samples taken more than 12 hs after the last rhGH injection between 0800–0900 h after an overnight fast. GHBP was measured by using high-pressure liquid chromatography gel filtration as described by Tar et al. (8). Serum IGF-I was assayed after separation from IGFBP by chromatography in acid conditions. IGF-I content was measured by RIA with polyclonal IGF-I antiserum provided by P. Chatelain (Lyon, France) and 125I-IGF-I (NEN, Les Ulis, France). rhIGF-I was used as standard. IGFBP-3 was measured directly in serum by using a commercial RIA kit (DSL, Ciba Corning, Chiron Diagnostic, Eragny, France). Plasma amino acids were measured by ion-exchange chromatography.
An OGTT (glucose 2 g/kg; measurements of plasma glucose and serum insulin levels at 0, 30, 60, and 120 min) was done after an overnight fast. Insulin levels were measured by RIA (Phadeseph insulin RIA, Kabi Pharmacia Diagnostics, Uppsala, Sweden). The A1c fraction of glycosylated hemoglobin (provided by Dr. R. Ducrocq, Hôpital Robert Debré) was measured by high-performance liquid chromatography.
Ethical approval
The study was approved by the Paris-Saint Louis ethics committee. Informed parental and patient consent were obtained in every case, and the study was conducted in accordance with French law on clinical research.
Statistical analysis
Values before, during, and after treatment were compared by using Student’s paired t test.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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As shown in Table 1
, all the patients were extremely short
(standing height ranged from -2.5 to -8 SD score for CA)
and had a very low GV. Their body weight (mean -1.9 SD
score for CA) was less reduced, reflecting the weight excess of these
children on long-term GC treatment. For a mean CA of 09 yr and 10
m, mean bone age was 7 yr and 5 m (range, 4 yr and 2 m to 11
yr and 6 m). Therefore, the mean bone age delay for CA was 2 yr
and 4 m (range, -5 yr to -1 yr).
The results of the GH-somatomedin axis investigations are shown in
Table 1. Stimulated GH secretion was normal except in one patient.
Spontaneous nocturnal secretion was below -2 SD score in 7
of the 14 patients. GHBP plasma levels were normal in all the patients
but were usually at the lower end of the normal range. The values of
IGF-I were normal in 12 and low in 2 of the 14 patients. IGFBP-3 plasma
concentrations were normal in all the patients.
Effect of rhGH treatment on growth parameters
During the 1-yr treatment period, mean GV increased from 1.9–5.4
cm/yr (P = 0.0001). As shown in Fig. 1, rhGH administration increased GV in
all the patients, although the magnitude of this effect varied markedly
from one patient to another. After 12 months, rhGH treatment was
discontinued, and 11 children were monitored for another year. GV
returned to pretreatment values (Fig. 1, mean GV of these 11 patients:
1.1 cm/yr). We found a highly significant inverse correlation (r =
0,7; P = 0,003) between GV during treatment and
prednisone dosage.
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shows changes in mean IGF-I and
IGFBP-3 plasma levels during the year on rhGH treatment. IGF-I and
IGFBP-3 plasma levels increased significantly as early as 1 month after
the onset of rhGH treatment and remained above normal throughout the
year of treatment. The mean IGF-I/IGFBP-3 ratio increased from 0.028
before treatment to 0.049 at 1 month (P < 0,01) and
remained stable during the year on treatment. GHBP levels remained
stable during treatment (results not shown). When rhGH was stopped,
IGF-I and IGFBP-3 returned to pretreatment values. The mean
IGF-I/IGFBP-3 ratio decreased from 0.047 to 0.024 1 yr after
discontinuation of rhGH treatment (P < 0,01), which
was similar to the pretreatment value.
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summarizes auxological data
during the 2 yr of follow-up. Mean standing height was not different
from baseline after 1 yr of GH treatment. During the 2nd yr (off
treatment), GV fell to pretreatment values. As a consequence, height
SD score at 2 yr was significantly lower than before
treatment. The relative weight excess, which was reduced during rhGH
treatment, increased strongly during the year after treatment
cessation.
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bone age/chronological
age ratio was observed (results not shown). All the patients remained
in pubertal stage I during the year on treatment, and two patients
showed the first signs of puberty during the second year (off
treatment). Effect of rhGH treatment on nutrition and metabolism
Most of the children were malnourished, as reflected by a low calorie intake for age (mean, 1305 kcal/day; range, 970-1990). Calorie intake increased slightly during the year on treatment (mean, 1305 kcal/day before treatment, 1404 kcal/day after 6 months, and 1342 kcal/day after 12 months), but this increase was not significant. We also measured the amino acid profile and free fatty acid plasma levels after a 12- to 15-h fast in all the patients and found no significant changes (results not shown).
Lean and fat mass was evaluated by means of DEXA (Table 2). Mean lean mass increased by 12%, and
mean fat mass fell by 20%. The same trends were seen in all the
patients, but values showed marked interindividual variability. After
treatment cessation, DEXA examinations showed that fat mass again
increased markedly (+87%). This emphasized the rapid reappearance of
clinical Cushing’s-like aspects that was observed in most patients.
Total lean mass also increased (+7%) but less so than during the year
on treatment; percent lean mass again fell.
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Glucose tolerance was evaluated by OGTT and HbA1c measurements
(Table 3). Compared with baseline values,
glycemia on rhGH treatment was slightly increased in the fasting state
and after a glucose load, but the differences were not significant.
Glycosylated hemoglobin increased significantly to above our upper
limit of normal in 8 of the 14 patients after one year of rhGH
treatment. Increased serum insulin levels was also observed in all 14
patients, both in the fasting state and after an oral glucose load.
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Other effects of rhGH treatment
GH had no clinical impact on the arthritis. Some parents reported an improvement in their children’s well-being during the year on treatment, but no objective assessment was made. The absence of any significant change in inflammatory activity is reflected by the stability of GC doses (mean, 8.14 mg/kg per day before treatment, 8.48 mg/kg per day after 6 months, and 8.58 mg/kg per day after 12 months; not significant) and the stability of the ESR (mean, 58 before treatment, 78 after 6 months, and 54 after 12 months; not significant).
Three children complained of muscle pain during the first few weeks of GH treatment, but this disappeared spontaneously. None of the patients complained of headache. No worsening of scoliosis was noted on clinical and/or radiological evaluation, despite the fact that some of the patients had severe scoliosis before GH treatment. One patient had osteochondritis of the hip, but this complication is frequent in JCA, and we thus decided to continue rhGH treatment; the lesions consolidated. One patient had marked proteinuria with nephrotic syndrome at the end of GH treatment. The proteinuria regressed spontaneously and kidney biopsy showed no specific lesions.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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) showed great variability. Only three patients had a GV
above +2 SD score for CA, i.e. partial catch-up
growth, and six patients had a GV below -2 SD score for
CA. Treatment cessation was followed by a return of GV to pretreatment
values. Overall, height retardation (in SD score for CA)
stabilized during the year on treatment and worsened again when
treatment was stopped (Fig. 3). The metabolic actions of GH may be divided into direct effects and those that occur indirectly after modulation of other mediators such as IGFs and IGFBP. IGFBP-3 forms a complex with IGF-I and binds circulating IGF. It could act as a carrier protein and intravascular store for IGF-I, regulating the actions of the latter. Low IGF-I and low IGFBP-3 levels have been found in catabolic states (9), and a substantial increase in serum IGF-I concentrations may reverse catabolism (10). Normal levels of somatomedins have been described in patients with Cushing’s syndrome and those treated with GC (11). However, such patients may have a reduction in somatomedin biological activity (11, 12, 13). Before rhGH treatment the levels of IGF-I in our patients were at the low end of the normal range, possibly reflecting resistance to GH. We found a negative correlation (r = 0.56, P < 0.05) between pretreatment IGF-I levels and the GV response to treatment demonstrating the importance of GH-IGF-I axis anomalies in the understanding of abnormal growth in these patients. This resistance does not seem to be caused by low GH receptor expression, because GHBP levels, which are thought to reflect GH receptor levels, were normal in most of the children. The GV improvement in our patients was associated with an increase in IGF-I and IGFBP-3 plasma levels to above-normal values, and also with an increase in IGF-I/IGFBP-3 ratio, demonstrating increased free IGF-I and therefore IGF-I bioavailability.
The reasons for growth retardation in JCA are multifactorial and include the chronic inflammatory state, bone and joint lesions, and undernutrition. The severe complications of active systemic JCA in terms of growth and metabolism are exacerbated by GC therapy. The negative correlation obtained between GV and GC dosage during treatment emphasizes the deleterious effect of GC dose on GH-IGF-I axis. The mechanism of linear growth inhibition by GC has not been defined. In vitro, GC can potentiate GH synthesis and release by cultured pituitary cells (14, 15), whereas results obtained in vivo are contradictory. Some authors have found inhibitory effects of GC on GH secretion (16), whereas others have observed no significant abnormality of GH secretion in GC-treated children (17, 18, 19). Furthermore, no correlation has been found between stimulated GH secretion and growth retardation in children treated with GC (20). It looks as though GC may affect not so much the level of GH secretion, but rather the nycthemeral GH secretion profile, resulting in delayed and attenuated nocturnal GH secretion peaks (21), which are known to be of particular importance for children’s growth. Butenandt et al. (2) described reduced secretion of GH in children with JCA treated with GC. We and others (5, 22, 23) have found a normal pharmacologically stimulated GH secretion peak. However, the spontaneous nocturnal GH secretion profile was disturbed in half our patients, with an attenuation of nocturnal GH peaks that may contribute to growth retardation.
GH treatment can improve growth in children receiving GC therapy after renal or hepatic transplants (24). GH treatment was first advocated some time ago for patients with JCA (1), but few studies have been reported (2, 3, 4, 5, 6). An increase in GV was observed in most patients in these studies and in all our patients. However, the heterogeneity of the GV response to rhGH treatment in our study must be emphasized. No criteria predictive of this response were found, except for low pretreatment plasma levels of IGF-I. The two patients (patients 3 and 13) who had catch-up growth (GV of 9.3 and 10.2 cm/yr) during the year on treatment had low IGF-I levels before treatment (64 and 26 ng/mL, respectively).
Because growth rates returned to the normal range but were not markedly
above normal, with skeletal maturation paralleling change in CA, rhGH
treatment prevented further height SD score deterioration
but no catch-up growth. However, stabilization of the children’s
position on the growth curve indicates a beneficial response to rhGH.
Figure 3 confirms that rhGH treatment may stop the statural
deterioration when statural deterioration continues after cessation of
treatment.
The contribution of JCA disease activity to changes in growth is difficult to quantify. None of our patients had spontaneous remissions from the disease during the year of treatment, and their chronic inflammatory disease may be considered stable as reflected by the stable doses of steroids and a stable mean ESR. All the children remained prepubertal during the year of treatment, again suggesting that the observed effects were attributable to rhGH treatment.
Patients treated with GCs for long periods have protein wasting (25) and may have severe losses of body protein (26), mainly caused by an increase in proteolysis (27, 28). In addition to its effects on growth rates, rhGH also increases muscle mass in humans (29). Treatment with rhGH may improve the nitrogen balance in hypercatabolic burn patients (30), normal volunteers during hypocaloric intravenous feeding (31), and patients on parenteral nutrition (32). Studies using isotope tracers have shown that GH can prevent the catabolic effects of steroids in healthy adult volunteers (33, 34) and may counteract the catabolic effect of excess endogenous steroids in Cushing’s syndrome (35). Our results confirm that GH therapy may have anabolic protein-sparing effects, even in a catabolic state as severe as active systemic JCA treated with GC. This effect may be explained by the combined protein-sparing properties of elevated concentrations of GH, increments in IGF-I and IGFBP-3, and increases in insulin and lipid intermediates in blood.
The lipolytic effect of GH is well known. GH may increase free fatty acid concentrations in a dose-dependent manner, and increases whole body lipid oxidation in healthy volunteers, diabetic patients, and trauma patients (36, 37, 38). GH may also limit lipid storage by reducing lipoprotein lipase activity in fat (39). Children (40) and adults (41) with GH deficiency have an excess in body fat, which is reduced by GH treatment. Our results show that GH may counterbalance the combined antilipolytic actions of GC and hyperinsulinemia and lead to a drastic reduction in the excess of fat mass induced jointly by JCA and GC treatment. These modifications are important, because they counter the Cushingoid appearance of the children, and are considered by the family to provide an important psychological benefit. Furthermore, this lipolytic effect may be of value in catabolic patients by preserving protein and carbohydrate stores.
Many parents reported that their children showed an increased exercise capacity during the year of GH treatment. Such an effect of GH therapy on well-being and quality of life has been described in GH-deficient patients (41) and in Prader-Willi syndrome (42). Although this is a subjective observation, it may be of particular interest in children with highly reduced activity, as in JCA, and should be objectively assessed in further studies.
Numerous studies have shown the ability of GH to impair insulin sensitivity (43, 44). Postabsorptive glucose metabolism is influenced by GH. Diabetes mellitus has occasionally been reported in patients treated with rhGH (45), but GH treatment alone rarely produces significant changes in glucose tolerance, even in children at risk of diabetes such as girls with Turner’s syndrome (46). In Cushing’s syndrome, the additional effects of excess endogenous GC and treatment with exogenous rhGH may induce resistance to insulin, reflected by an increase in glucose, insulin, and C-peptide blood levels (35). In patients who have the risks of both exogenous GC and GH therapies, we and others (4) have observed a small but significant rise in blood glucose values and a more marked rise in blood insulin values but no diabetes. The risk of diabetes and the consequences of long-term hyperinsulinism will have to be evaluated in long-term studies.
Overall, our data confirm that rhGH therapy may counteract the harmful effects of GC on growth and metabolism, even in patients with systemic JCA. Larger and longer controlled studies are needed to determine the long-term risks and to confirm the benefits of GH therapy for GC-dependent children. After completion of this study, the 14 patients were offered inclusion in a new 3-yr rhGH therapeutic trial, and all have agreed to do so.
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Acknowledgments |
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Footnotes |
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Received August 6, 1997.
Revised October 23, 1997.
Accepted November 4, 1997.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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