Intersubject responsiveness of high-affinity growth hormone (GH)-binding protein (GHBP) to long-term GH replacement therapy.

Abstract

In adult growth hormone deficiency (GHD) syndrome responsiveness to GH replacement therapy is reported to vary considerably. The underlying mechanisms, however, are not well understood. The aim of this study was to investigate which baseline variables determine the reported variable intersubject responsiveness of high-affinity GH-binding protein (GHBP) to GH replacement therapy. In the setting of a double blind study over 12 months with placebo control over the first 6 months, we analyzed the interrelationship between a number of baseline variables, which vary considerably amongst subjects, and the GHBP response to GH replacement in 31 GHD adults (21 males and 10 females). The following variables were investigated: age, gender, duration of GHD, body composition, serum levels of high-affinity GHBP, insulin-like growth factor-1 (IGF-1), and IGF-binding protein-3 (IGFBP-3). The results showed that in the 6 months treated group of 16 patients (11 males, 5 females), serum IGF-1 increased from 87 ng/ml (range: 26 to 173) to 250 (range: 62 to 467) (p<0.01) and GHBP increased from 1,302 pmol/l (range: 845 to 1,m960) to 1418 (range: 941 to 2,025) (p=0.04). Both parameters showed a significant time effect (within-subjects) (p<0.001). In the 12 months treated group of 15 patients (10 males, 5 females), serum IGF-1 increased from 92 ng/ml (range: 20 to 180) to 272 (range: 45 to 491) (p<0.01), whereas GHBP did not show a significant change: from 1,186 pmol/l (range: 660 to 1,690) to 1,252 (range: 580 to 1,890) (p=0.87). Also no significant time effect (within-subjects) was observed for GHBP (p=0.06). Step-wise multiple regression analyses revealed that during the 6 months placebo period baseline GHBP explained 83% of the variance in post-placebo GHBP, whereas the variance in post-treatment GHBP could be accurately predicted (adjusted R2=0.93) from baseline GHBP and body fat mass, irrespective of the duration of GH treatment. No other baseline variables contributed independently to the GHBP response, with the exception of IGFBP-3, which showed a small, but significant contribution in females, but not in males. These findings indicate that the variable intersubject responsiveness of GHBP to GH replacement therapy is mainly due to differences in baseline body fat mass amongst adult GHD patients, and that in female patients a relatively low baseline IGFBP-3 contributes to a rise in serum GHBP after GH treatment. The clinical relevance of measuring GHBP in adult GHD patients is limited to the first screening step to diagnose GHD, because long-term GH therapy tends to restore serum GHBP to pretreatment levels.