Recombinant human growth hormone (rhGH) therapy is used in the long-term treatment of children with growth disorders, but there is considerable treatment response variability. The exon 3-deleted growth hormone receptor polymorphism (GHR(d3)) may account for some of this variability. The authors performed a systematic review (to April 2011), including investigator-only data, to quantify the effects of the GHR(fl-d3) and GHR(d3-d3) genotypes on rhGH therapy response and used a recently established Bayesian inheritance model-free approach to meta-analyze the data. The primary outcome was the 1-year change-in-height standard-deviation score for the 2 genotypes. Eighteen data sets from 12 studies (1,527 children) were included. After several prior assumptions were tested, the most appropriate inheritance model was codominant (posterior probability = 0.93). Compared with noncarriers, carriers had median differences in 1-year change-in-height standard-deviation score of 0.09 (95% credible interval (CrI): 0.01, 0.17) for GHR(fl-d3) and of 0.14 (95% CrI: 0.02, 0.26) for GHR(d3-d3). However, the between-study standard deviation of 0.18 (95% CrI: 0.10, 0.33) was considerable. The authors tested by meta-regression for potential modifiers and found no substantial influence. They conclude that 1) the GHR(d3) polymorphism inheritance is codominant, contrasting with previous reports; 2) GHR(d3) genotypes account for modest increases in rhGH effects in children; and 3) considerable unexplained variability in responsiveness remains.
Westwood M, Maqsood AR, Solomon M, Whatmore AJ, Davis JR, Baxter RC, Gevers EF, Robinson IC, Clayton PE. The effect of different patterns of growth hormone administration on the IGF axis and somatic and skeletal growth of the dwarf rat. Am J Physiol Endocrinol Metab 298: E467-E476, 2010. First published October 27, 2009 doi:10.1152/ajpendo.00234.2009.-Normal childhood growth is determined by ultradian and infradian variations in GH secretion, yet GH treatment of children with short stature is restricted to daily fixed doses. We have used GH-deficient dwarf rats to determine whether variable GH dose regimens promote growth more effectively than fixed doses. Animals were treated with saline or 4.2 mg of recombinant bovine GH given as 1) 700 g/wk in 100 g/day doses, 2) alternating weekly doses of 966 (138 g/day) or 434 g (62 g/day), or 3) 700 g/wk in randomized daily doses (5-250 g/day). Body weight and length were measured weekly. Femur and tibia lengths and internal organ, fat pad, and muscle weights were recorded at the end of the study (6 wk); blood was collected for IGF axis measurements. GH promoted femur [F(3,60) 60) ϭ 6.70, P Ͻ 0.05] levels. IGF-I levels correlated with final weight (r ϭ 0.45, P Ͻ 0.05) and length (r ϭ 0.284, P Ͻ 0.05) in the whole cohort, but within each group, growth parameters correlated with serum IGF-I only in animals treated with random GH doses. The variable regimens promoted femur length (P Ͻ 0.05) and muscle (P Ͻ 0.05) and kidney (P Ͻ 0.05) weight more effectively than treatment with the fixed regimen. This study demonstrates that aspects of growth are improved following introduction of infradian variation to GH treatment in a GH-deficient model. The data suggest that varying the pattern of GH doses administered to children may enhance growth performance without increasing the overall GH dose.insulin-like growth factor; growth hormone deficiency; infradian; insulin-like growth factor-binding protein; acid-labile subunit GROWTH HORMONE (GH) is the major regulator of postnatal body growth (46). Consequently, GH deficiency (GHD) during childhood results in severe growth retardation and, if untreated, marked impairment of adult height. Therefore, children with GHD are offered replacement therapy, and, if given in accordance with the published guidelines of 25-50 g·kg Ϫ1 ·day Ϫ1(31), many achieve an adult height within the normal range. However, this is not always the case; in a group of children with idiopathic GHD, treatment with biosynthetic GH resulted in a mean height standard deviation score of Ϫ0.7, which was 0.45 SD less than the parental target height of Ϫ0.25 (7). GH is also used in the management of other growth problems, for example, in idiopathic short stature and Turner syndrome. Overall, therapy is advantageous, but in these groups there is also considerable variability in the response to GH, and some children remain short even with treatment (33). Thus these studies demonstrate that although GH administration is beneficial for some children, the therapeutic potentia...
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