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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0049
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 6 3435-3439
Copyright © 2005 by The Endocrine Society

Neutrophil Count in Small-for-Gestational Age Children: Contrasting Effects of Metformin and Growth Hormone Therapy

Lourdes Ibáñez, Alina Fucci, Carme Valls, Ken Ong, David Dunger and Francis de Zegher

Endocrinology Unit (L.I., A.F.) and Hormonal Laboratory (C.V.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain; Department of Pediatrics (K.O., D.D.), University of Cambridge, Cambridge CB2 2QQ, United Kingdom; and Department of Pediatrics (F.d.Z.), University of Leuven, 3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Lourdes Ibáñez, M.D., Ph.D., Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Passeig de Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. E-mail: libanez{at}hsjdbcn.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
A minority of children born small for gestational age (SGA) maintain a slow weight gain and a short stature (SS). At the other end of the spectrum are SGA children who show rapid postnatal weight gain and catch-up growth; these subjects may develop hyperinsulinemia, exaggerated adrenarche with precocious pubarche (PP), and an associated proinflammatory state with raised IL-6 and reduced adiponectin levels.

Metformin therapy in SGA-PP girls attenuates the hyperinsulinemia, the adrenal androgen excess, and the proinflammatory state. In contrast, GH therapy in SGA-SS children promotes height gain but may induce hyperinsulinemia. Both groups are associated with increased risk markers for future cardiovascular disease. Therefore, we studied markers of inflammation in both SGA subpopulations at baseline and after their respectively corrective therapies.

SGA-PP girls (n = 33; mean age, 8 yr; body mass index, 18.5 kg/m2) were randomized to remain untreated or to receive metformin (425 mg/d) for 6 months. SGA-SS children (n = 29; mean age, 7 yr; body mass index, 14.7 kg/m2) were randomly assigned to remain untreated or to receive GH (60 µg/kg/d). In SGA-PP girls, the mean neutrophil count (4.0 x 1000/mm3) was more than 2 SD above the mean reference level (2.8 x 1000/mm3, P < 0.001); this remained stable over 6 months in untreated girls but dropped in metformin-treated girls by –1.1 x 1000/mm3 (P = 0.002).

In SGA-SS children, neutrophil counts were also higher at baseline (3.3 x 1000/mm3, P < 0.01). This remained stable in untreated children but rose in GH-treated children by +1.1 x 1000/mm3 (P = 0.004). GH-treated children also showed a rise in circulating IL-6 and dehydroepiandrosterone-sulfate levels and a fall in adiponectin levels.

In conclusion, neutrophil counts were elevated in SGA children. In SGA girls with PP, the present results corroborate the antiinflammatory benefits of metformin therapy. In contrast, high-dose GH therapy in short SGA children may increase neutrophil counts and lead to a less favorable adipocytokine profile. Future studies with combined GH plus metformin treatment in short SGA children may clarify whether insulin resistance is a mechanism linking GH therapy to markers of inflammation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AMONG CHILDREN BORN small for gestational age (SGA), there is a minority (~10%) that fails to catch up in growth and maintains a short stature (SS) and a low weight (1, 2). In contrast, another minority presents rapid catch-up growth with excessive weight gain; these children develop, by late infancy (3), a variant of hyperinsulinemia that may be followed by an exaggerated adrenarche [high circulating dehydroepiandrosterone-sulfate (DHEAS) for age] and be expressed as precocious pubarche (PP; pubic hair at <8 yr) in genetically predisposed SGA girls (4, 5, 6, 7, 8, 9). For these children at different ends of the SGA spectrum (Table 1Go, left columns), divergent therapies with GH or metformin have been developed independently. Metformin has net insulin-sensitizing effects, whereas GH (in high dose) has net insulin-desensitizing effects.


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  		TABLE 1. Summary of baseline differences between hyperinsulinemic and short SGA children and of the opposite effects of metformin and GH therapy in these respective groups

 
Metformin therapy in SGA girls with PP attenuates not only the hyperinsulinemia, the adrenal androgen excess, the dyslipidemia, and the body adiposity, but also the proinflammatory state, as judged by IL-6 and adiponectin (10) (Table 1Go); it is unknown whether the leukocyte count—a time-honored marker of inflammation—is abnormal in these girls and, if so, whether it is normalized by metformin therapy.

GH therapy in SGA children with SS promotes height gain up to adult stature (11) and induces a reversible state of euglycemic hyperinsulinemia (12, 13) (Table 1Go); it is unknown whether GH therapy is associated with shifts in leukocyte count or in circulating adipocytokines.

In SGA girls with PP, we measured the leukocyte count and studied the effects of insulin-sensitizing therapy with metformin; in SGA children with SS, we determined the leukocyte count and assessed the effects of insulin-desensitizing GH therapy on IL-6, adiponectin, and DHEAS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study populations and design

Metformin study. The children enrolled in this open-labeled, randomized study have been described in detail (10). In brief, the population consisted of 33 prepubertal girls (age 8.0 ± 0.1 yr; mean ± SEM) who had a low weight at term birth (2.4 ± 0.08 kg) and who subsequently presented with high-normal body mass index (BMI; 18.5 ± 0.3 kg/m2; all <21 kg/m2) and PP attributable to exaggerated adrenarche (DHEAS 101 ± 7 µg/dl). These girls were randomized to remain untreated for 6 months or to receive metformin (425 mg/d) once daily at dinner. Leukocyte count and differentiation were among the safety indices assessed at 0 and 6 months; baseline leukocyte results were compared with local references from healthy, prepubertal children of similar age.

GH study. The population consisted of 29 prepubertal children (13 girls and 16 boys) followed at Barcelona University Hospital within an open-labeled, controlled Spanish GH trial (n = 82) conducted from 1999–2003.

Inclusion criteria for the trial were: birth weight and/or length below percentile 10 for gestational age (14); age 2.0–8.0 yr at start; height SDS for age below –2.5 SD according to Tanner references applicable to Catalan children (15, 16); height velocity less than 0 SD for age (15); prepuberty, defined as breast stage I for girls and testicular volume less than 4 ml for boys (17, 18); and serum GH concentration greater than 10 µg/ml, either spontaneously or during an L-dopa or clonidine test.

Exclusion criteria were known endocrine-metabolic disorders, chromosomal anomalies, previous or concomitant irradiation, anabolic steroid therapy, severe chronic disease, mental retardation, Silver-Rusell syndrome, and previous or present use of medication potentially interfering with GH treatment.

At study start, the subcohort composing the present study had a chronological age between 6 and 9 yr—this is the age range in which serum levels of adrenal androgens normally start rising (19).

Children were randomly assigned to remain untreated or to receive daily sc injections of recombinant human GH (Norditropin; Novo Nordisk, Bagsvaerd, Denmark) in an evening dose of 60 µg/kg. The study visits at 0 and 6 months included an auxological evaluation and endocrine-adipocytokine assessments in fasting state. Height (Harpenden stadiometer) and weight were measured by one observer; blood leukocyte count and glucose were measured, as well as serum insulin, IGF-I, IL-6, adiponectin, and DHEAS. Fasting insulin sensitivity was estimated from fasting insulin and glucose levels using the homeostasis model of assessment (HOMA-CIGMA Calculator program version 2.00) (20). Baseline leukocyte results were compared with local references from healthy, prepubertal children of similar age; hormone and adipocytokine levels were compared with those from children of similar age, recruited among patients admitted for minor, elective surgery.

Assays, statistics, and ethics

Leukocyte count was assessed by automated cell counter (ABX Pentra 120, ABX Diagnostics; Montpellier, France) calibrated with an ABX Minotrol 16 (ABX Diagnostics); the intraassay coefficient of variation (CV) determined on five replicates of each leukocyte measurement was 1% or less. Glucose was measured by the glucose oxidase method; immunoreactive insulin was assayed by IMX (Abbott, Santa Clara, CA); intra- and interassay CV were 4.7 and 7.2%. DHEAS, IGF-I, and IL-6 were measured by immunochemiluminescence (IMMULITE 2000; Diagnostic Products, Los Angeles, CA). IL-6 had a lower detection limit of 100 fg/ml, intra- and interassay CV were 3.5 and 5.1%, the interassay CV for DHEAS was less than 10%, and the lower detection limit was 0.12 µg/ml (0.32 nmol/liter). The lower detection limit for IGF-I was 25 ng/ml, and intra- and interassay CV were 8.6 and 9%. Adiponectin was measured by RIA (Linco Research Inc., St. Charles, MO); intra- and interassay CV were 6.2 and 6.9%. Samples were kept frozen at –20 C until assay. Two-sided Student’s t tests (paired or unpaired, as appropriate) were used for statistical comparisons; per variable, only one comparison was performed; significance level was set at P < 0.05.

The study protocols and collection of normal control samples were approved by the Institutional Review Board of Barcelona University, Hospital of Sant Joan de Déu (Barcelona, Spain). Informed consent was obtained from parents and assent from children.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Metformin study

In SGA + PP girls, the leukocyte count was high-normal at baseline; on average, the absolute neutrophil count was more than 2 SD above the reference mean (Table 2Go). In untreated girls, the high neutrophil count remained stable; in metformin-treated girls, the mean neutrophil count dropped by more than 1000 cells/mm3 (Fig. 1Go). Counts of lymphocytes (Table 2Go), monocytes, basophils, and eosinophils (data not shown) were normal at baseline and remained so in both untreated and metformin-treated girls.


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  		TABLE 2. Baseline values in neutrophil and lymphocyte counts and changes (0–6 months) after randomized treatments with metformin and GH in SGA children with respectively PP or SS

 


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  		FIG. 1. Leukocyte counts (upper panels) and changes in neutrophil count (lower panels) are shown in SGA girls with PP (SGA + PP; left) and SGA children with SS (SGA + SS; right). In the upper panels, the dotted line and the upper limit of the shaded zone indicate the mean and +2 SD limit of the reference range (Table 2Go). SGA + PP girls were randomized to stay untreated (n = 17) or to receive metformin (n = 16; 425 mg/d) for 6 months. SGA + SS children were randomized to remain untreated (n = 13) or to receive GH (n = 16; 60 µg/kg/d) for 6 months. Leukocyte count was high-normal at start in both SGA groups; metformin therapy was associated with a drop toward mean reference level, and GH therapy was accompanied by an additional elevation (***, P < 0.005 vs. baseline). The raised neutrophil count at start (Table 2Go) decreases in SGA + PP girls on metformin, and it increases further in SGA + SS children on GH (***, P < 0.005 vs. untreated).

 
GH study

In SGA + SS children, the leukocyte count was also high-normal at start; both the neutrophil and the lymphocyte counts contributed to this relative rise (Table 2Go); and monocyte, basophil, and eosinophil counts (not shown) were normal at baseline and remained so in both subgroups. In untreated children, the neutrophil and lymphocyte counts were stable; in GH-treated children, the neutrophil count rose to an average level more than 3 SD above the reference mean, whereas lymphocyte count did not change (Table 2Go; Fig. 1Go).

At study start, results of endocrine-metabolic variables and adipocytokines were comparable between randomized subgroups (Table 3Go). After 6 months, GH-treated children presented more height and weight gain, a higher IGF-I rise, and a less insulin-sensitive state than untreated children, as expected. GH-treated children also displayed an increment in circulating IL-6 and DHEAS and a consistent fall in circulating adiponectin. Changes in all variables, including DHEAS and adipocytokine levels, were similar in boys and girls (data not shown). None of the children developed PP.


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  		TABLE 3. Clinical and endocrine-metabolic results in short SGA children (n = 29; term birth weight, 2.3 ± 0.1 kg) who were randomized either to remain untreated (n = 13) or to receive GH treatment (n = 16; 60 µg/kg/d) for 6 months

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Neutrophil counts were elevated in SGA children with PP or SS; they were lowered with metformin in SGA-PP girls and heightened further with GH in SGA-SS children.

In SGA-PP girls, the high neutrophil count is known to be accompanied by proinflammatory shifts in circulating IL-6 and adiponectin (10). Hence, the present results corroborate the antiinflammatory benefit of giving metformin to SGA-PP girls, who constitute a group at high-risk for evolvement toward the next stage of hyperinsulinemic hyperandrogenism, namely polycystic ovary syndrome (6).

In SGA-SS children, high-dose GH therapy was accompanied by a decrease of insulin sensitivity, by an exaggerated rise in DHEAS levels (without PP), an increment of IL-6, and a fall of adiponectin levels. The extent to which untreated SGA-SS children are insulin-resistant is currently unclear (7, 21, 22); in some cohorts, hyperinsulinemia and reduced insulin sensitivity have been associated with elevated levels of GH in the copresence of normal IGF-I concentrations (23). The present study population was not particularly insulin-resistant at baseline, but their index of insulin sensitivity dropped by half within 6 months, presumably due to the insulin-desensitizing effects of GH, either direct or indirect through increase in circulating free fatty acids (24). Because GH-induced insulin-desensitization is in prepubertal SGA children reversible upon cessation of GH treatment (12) and because the combination of exaggerated adrenarche (with PP), high IL-6, and low adiponectin can be attenuated by insulin-sensitizing metformin therapy (10), it is plausible that compensatory hyperinsulinemia is among the mediators of the DHEAS and IL-6 rises and of the adiponectin fall observed on high-dose GH treatment.

In SGA-SS children on GH, the neutrophil count and the adipocytokine pattern changed toward those found in other insulin-resistant, proinflammatory states (25, 26, 27, 28). Data linking GH to the production of inflammatory cytokines are variable, depending on the animal or human models studied. In vitro, GH increases production of IL-1 and TNF-{alpha} from human mononuclear cells (29), and recent studies have reported that GH stimulates production of mannose-binding lectin, an innate immune defense plasma protein that activates the complement cascade and inflammation (30, 31). It is suggested that overactivation of the systemic inflammatory response could contribute to higher mortality in GH-treated critically ill patients (32). The relevance of this to the SGA-SS is yet speculative. Such a proinflammatory state could be associated with central adiposity and cardiovascular risk (28, 33, 34, 35, 36, 37), but longer-term studies are needed to show whether these proinflammatory changes might affect endothelial function and cardiovascular risk. Our observation of opposite effects of GH therapy and metformin on endocrine markers, neutrophil count, and other indices of low-grade inflammation (Table 1Go, right columns) suggest that hyperinsulinemic insulin resistance is a plausible modulator of this leukocyte and adipocytokine profile. Future studies of combined GH plus metformin treatment in SGA-SS children may contribute to clarify whether insulin resistance is a mechanism linking GH therapy to markers of inflammation.

In line with an earlier report (37), we observed no PP during GH treatment of short SGA children; in the same report, no associations were found between GH therapy and adrenarche, but a wide age range was studied over a relatively long time. In contrast, our study design with a narrow age range at start (6–9 yr) and a shorter study duration (6 months) may have allowed a more readily detectable differentiation between a rise in DHEAS related to GH treatment vs. an increment attributable to advancing age. We did not observe a significant change in DHEAS levels in children randomized to stay untreated; therefore, it is unlikely that the disclosed DHEAS rise in GH-treated children reflects chance development of adrenarche. In other populations, GH therapy in short SGA children has been found to have no influence on pubertal milestones (38); the relatively short duration of our study does not allow to infer conclusions in relation to the impact of the increase in DHEAS levels on prepubertal bone maturation or on the timing of the onset of puberty. Further challenges will be to verify whether the rise of the neutrophil count, the increments of DHEAS and IL-6, and the fall of adiponectin persist over time, whether they are specific for SGA children and/or for high-dose GH therapy, and whether they are reversible upon cessation of GH therapy.


   Acknowledgments
 
We thank Montserrat Gallart for hormone measurements.


   Footnotes
 
F.d.Z. is a Clinical Research Investigator of the Fund for Scientific Research (Flanders, Belgium).

First Published Online March 8, 2005

Abbreviations: BMI, Body mass index; CV, coefficient(s) of variation; DHEAS, dehydroepiandrosterone-sulfate; PP, precocious pubarche; SGA, small for gestational age; SS, short stature.

Received January 11, 2005.

Accepted March 2, 2005.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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 J. Clin. Endocrinol. Metab.Home page
L. Ibanez, K. Ong, D. B. Dunger, and F. de Zegher
Early Development of Adiposity and Insulin Resistance after Catch-Up Weight Gain in Small-for-Gestational-Age Children
J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2153 - 2158.
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 J. Clin. Endocrinol. Metab.Home page
S. Srinivasan, G. R. Ambler, L. A. Baur, S. P. Garnett, M. Tepsa, F. Yap, G. M. Ward, and C. T. Cowell
Randomized, Controlled Trial of Metformin for Obesity and Insulin Resistance in Children and Adolescents: Improvement in Body Composition and Fasting Insulin
J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2074 - 2080.
[Abstract] [Full Text] [PDF]

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 PediatricsHome page
L. Ibanez, K. Ong, D. B. Dunger, and F. d. Zegher
Effects of Growth Hormone Treatment on Neutrophil Count in Children Born Small for Gestational Age
Pediatrics, May 1, 2006; 117(5): 1868 - 1869.
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