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Journal of Pediatric Endocrinology & Metabolism, 22,837-843 (2009)
Effect of Human Recombinant Growth Hormone Therapy on Circulating Levels of Erythropoietin and Granulocyte-Colony Stimulating Factor in Short Children Cristina Meazza, Irene Bonomelli, Sara Pagani, Paola Travaglino, Kamilia Laarej, Francesca Cantoni and Mauro Bozzola Paediatric Department, University ofPavia, Fondazione IRCCS San Matteo, Pavia, Italy ABSTRACT
INTRODUCTION
Several reports suggest a role of growth hormone (GH) in the regulation of the haematopoietic system, as regards the normal differentiation and function of blood cells. The aim of this study was to evaluate the influence of rhGH therapy on erythropoietin (Epo) and granulocyte-colony stimulating factor (G-CSF) levels in 18 prepubertal short children with idiopathic GH deficiency (GHD) (n = 8) or without GHD (n = 10), during the first year of treatment. In nonGHD children Epo levels significantly decreased and G-CSF levels increased from basal to 12 months of therapy, whereas in GHD children they did not change significantly. Circulating levels of G-CSF are significantly lower in GHD than in non-GHD children. In non-GHD children the number of red blood cells, haemoglobin and haematocrit values significantly increased after 1 year of rhGH treatment. rhGH therapy influences Epo and G-CSF levels in short nonGHD children, while it shows no effects in GHD children.
Several reports suggest a role of growth hormone (GH) in the regulation of the haematopoietic system1, as regards the normal differentiation and function of erythroid, myeloid and lymphoid cells2. A vast body of evidence demonstrates that GH and insulin-like growth factor-I (IGF-I) stimulate the growth of erythroid precursor cells in vitro and haematopoiesis in vivo3'4. Nevertheless, haematopoietic progenitors and mature blood cells have been shown to produce GH and IGF-I and to express receptors for these peptides5. Patients with GH deficiency (GHD) generally show haematopoietic precursor cells in the lower normal range but no anaemia, probably because local GH production by polymorphonuclear cells compensates for low pituitary GH concentrations. Studies in adults with GHD show a significant increase in erythroid and myeloid progenitor precursor cells and in individual haemoglobin (Hb) levels after 24 months of substitutive therapy6'7. In anaemic patients with adult GHD, short-term administration of rhGH is able to increase erythropoietin (Epo) levels and Hb concentrations, while long-term administration suppresses plasma Epo levels via negative feedback regulation by increased Hb concentrations8. Furthermore, GH stimulates the development and function of granulocytes9, and 10 months administration of rhGH in adults with GHD increases granulocytecolony stimulating factor (G-CSF) concentrations and neutrophil count, suggesting that GH might stimulate neutrophil production through G-CSF10. The few studies in children with GHD report that rhGH replacement normalizes Hb levels in anaemic patients11, while in children with normal blood cell count parameters it was confirmed that
KEY WORDS growth hormone, erythropoietin, granulocyte-colony stimulating factor, children, growth hormone deficiency Reprint address: Prof. Mauro Bozzola, M.D. Dipartimento di Scienze Pediatriche Universitä degli Studi di Pavia Fondazione IRCCS San Matteo Piazzale C. Golgi 2 27100 Pavia, Italy e-mail:
[email protected]
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C. MEAZZA ET AL.
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rhGH substitutive therapy has no additional effect on erythropoiesis12. Finally, a study on small for gestational age children demonstrated a positive effect of rhGH administration on neutrophil count13. The aim of this study was to evaluate the influence of rhGH therapy on Epo and G-CSF levels in prepubertal short children with or without complete GHD. This report should be considered as a pilot study on the relationship between plasma Epo and G-CSF levels and rhGH treatment in short children. PATIENTS AND METHODS Patients
Eight children (5 M, 3 F) with idiopathic GHD and 10 short children (8 M, 2 F) with normal GH secretion entered the study. All patients were prepubertal and remained prepubertal during the follow-up. The diagnosis of total GHD was established when Gil response to at least two pharmacological stimuli was lower than 5 ng/ml in the presence of short stature, reduced growth velocity and delayed bone age14. The other short children (non-GHD) showed auxological criteria suggestive of GHD but normal GH response to pharmacological stimuli (>10 ng/ml) and low GH bioactivity, as measured by Nb2 bioassay15. None of the patients had diabetes insipidus, chromosomal abnormalities, dysmorphic syndromes, intestinal malabsorption such as celiac disease, other chronic diseases or acquired GHD, after full clinical and laboratory evaluation. All patients showed normal thyroid and adrenal function. Magnetic resonance imaging (MRI) of the hypothalamus and pituitary region was normal in all patients. The main auxological and hormonal baseline findings of both GIID and non-GHD children are detailed in Table 1. According to the national recommendations for the use of rhGH in children, therapy was administered at the weekly dose of 0.25 mg/kg subcutaneously, divided into 6 daily doses in the evening, in both GHD and non-GHD children. The effectiveness of the first year of rhGH therapy was
assessed by the evaluation of height SDS, growth velocity and IGF-I levels. Height was measured using a Harpenden stadiometer, and expressed as standard deviation score (SDS) for chronological age. Anthropometric data and pubertal development stage were recorded according to Tanner and Whitehouse . Bone age was estimated according to the method of Greulich and Pyle and expressed as SDS17. Target height was calculated as sex-corrected mid-parental height and expressed in SDS. The study was approved by the ethics committee of the Institution and written informed consent was obtained from the children's parents. Blood samples from each patient were collected before and 3, 6 and 12 months after starting rhGH therapy. The blood was used to determine haemachrome and circulating levels of Epo and G-CSF. Methods
GH and IGF-I levels were assayed by an automated chemiluminescent assay system (Immulite, Diagnostic Products Corp, Los Angeles, CA, USA). Routine methods were used for haematological measurements. Serum Epo and G-CSF were measured by commercially available enzyme-linked immunosorbent assays (R&D Systems, Minneapolis, MN, USA); the minimum detectable concentrations by these assays were 2.5 mIU/ml for Epo and 1.25 pg/ml for G-CSF. Statistical analysis
The normal distribution of the variables was evaluated by Shapiro's test and the data are presented as medians and interquartile range (IQR) (25-75th percentiles); non-parametric tests were used for comparisons between groups (MannWhitney U-test) and to compare the changes of the same parameter within one group of patients during the first year of treatment (Friedman ANOVA test). A p value of less than 0.05 was considered to be statistically significant. All tests were two-sided. Analyses were performed with Statistica for Windows (StatSoft, Inc., 2004, Tulsa, OK, USA).
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rhGH THERAPY AND ERYTHROPOIETIN AND G-CSF
RESULTS
As shown in Table 1, the auxological and hormonal parameters were comparable between the two groups of patients before starting rhGH therapy, except for GH secretion that was reduced only in the GHD children. The effectiveness of rhGH therapy during the first year of treatment in all children was demonstrated by a significant (p
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