title: IGF-I and IGF binding protein-3 levels during initial GH dosage step-up are indicators of GH sensitivity in GH-deficient children and short children born small for gestational age.
abstract: BACKGROUND
  A stepwise increment of the GH dose is an approach aimed at avoiding adverse events. We investigated GH sensitivity by studying IGF-I and IGFBP-3 concentrations during the initial phase of GH treatment.
  
  
  METHODS
  Our investigation was part of the regular follow-up of prepubertal children with GH deficiency (GHD) (n = 31) and small for gestational age (SGA) (n = 23). Dosage was increased in three steps: one-third at the start, two-thirds after 14 days, and the full dose after 28 days (full dose: GHD = 28 microg/kg body weight (BW)/day; SGA = 60 microg/kg BW/day). Blood samples were taken on days 0, 14 and 28, as well as in conjunction with anthropometrical examinations after 3, 6 and 12 months. IGF-I and IGFBP-3 were measured by means of published in-house RIAs and age-related references were used to calculate standard deviation scores (SDS). Height velocity (cm/year) and Delta HT SDS were taken as growth response parameters.
  
  
  RESULTS
  Before GH treatment (GHD vs. SGA; median and p values): age (years) (6.6 vs. 6.0; n.s.), HT SDS (-2.6 vs. -3.2; p < 0.05); GH amount after stepping up (mug/kg BW/day) (28 vs. 60; p < 0.01); BW SDS (-0.5 vs. -2.9; p < 0.01); max. GH stimulated (microg/l) (5.6 vs. 10.8; p < 0.01); IGF-I SDS (-3.5 vs. -1.8; p < 0.01); IGFBP-3 SDS (-2.0 vs. 0.8; p < 0.01). After 1 year of GH therapy: HT velocity (cm/year) (9.8 vs. 9.6; n.s.), Delta HT SDS (0.9 vs. 0.9; n.s.); WT velocity (kg/year) (3.3 vs. 3.5; n.s.). Our results show that changes in growth similar to GHD could be induced in SGA by a dosage that was twice as high as the replacement dose given in GHD. GH dose and HT velocity did not correlate in both groups. IGF-I and IGFBP-3 increased as follows in GHD and SGA during stepping up of the dosage (ng/ml, GHD vs. SGA): at start, 54 vs. 89; at day 14, 78 vs. 132; at day 28, 90 vs. 167; at 3 months, 118 vs. 218. There was the same relationship between dose levels and absolute IGF-I concentrations in both groups. In terms of IGF-I SDS, the dose-response curve in SGA showed a shift to the right in comparison to GHD, thus indicating lower sensitivity to GH. The dynamics of IGF-I and IGFBP-3 differed, as IGFBP-3 peaked earlier (on day 28). In GHD, IGF-I SDS at 3 months was -0.7 vs. +0.9 in SGA. Near-identical levels were found for Delta IGF-I SDS and IGFBP-3 SDS above basal levels for each time-point investigated. First year HT velocity in GHD correlated negatively with basal IGF-I SDS (R(2) = 0.33; p <0.001) and basal IGFBP-3 (R(2) = 0.17; p <0.05) but did not correlate with the IGF-I increment during the 0- to 3-month period. Conversely, first year HT velocity correlated (+) in SGA with the IGF SDS increment during the 0- to 3-month period (R(2) = 0.26; p = <0.05). Height velocity in SGA, however, correlated neither with basal IGF-I and IGFBP-3 nor with the 0- to 3-month increments of IGFBP-3 SDS.
  
  
  CONCLUSIONS
  IGFs increase during initial GH therapy, thus raising questions about short-term IGF generation tests. (I) In terms of IGF generation, substantially lower sensitivity to GH was observable in SGA. (II) Higher GH sensitivity during first year catch-up growth is associated with GHD, but in SGA it is attributable to increases in IGF. A wider range of GH dosages needs to be explored in order to gain further insight into the relationship between GH dose, IGF levels, and growth. Monitoring IGFs is a practical means for exploring GH sensitivity during dosage stepping up.
authors.affiliation: Paediatric Endocrinology Section, University Children's Hospital, Tubingen, Germany. Michael.Ranke@med.uni-tuebingen.de
authors.forename: Michael B
authors.initials: MB
authors.lastname: Ranke
authors.forename: Richard
authors.initials: R
authors.lastname: Traunecker
authors.forename: David D
authors.initials: DD
authors.lastname: Martin
authors.forename: Roland
authors.initials: R
authors.lastname: Schweizer
authors.forename: C Philipp
authors.initials: CP
authors.lastname: Schwarze
authors.forename: Hartmut A
authors.initials: HA
authors.lastname: Wollmann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Binder
mesh_terms: D001827:Body Height / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006128:Growth / Q000187:drug effects; D013006:Growth Hormone / Q000008:administration & dosage / Q000627:therapeutic use*; D019382:Human Growth Hormone / Q000172:deficiency*; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone