Effects of recombinant human insulin-like growth factor I (IGF-I) therapy on the growth hormone-IGF system of a patient with a partial IGF-I gene deletion
C. Camacho-hubner et al., Effects of recombinant human insulin-like growth factor I (IGF-I) therapy on the growth hormone-IGF system of a patient with a partial IGF-I gene deletion, J CLIN END, 84(5), 1999, pp. 1611-1616
We have previously reported a 17.2-yr-old boy with severe growth retardatio
n and undetectable serum levels of insulin-like growth factor I(IGF-I) due
to a partial deletion of the IGF-I gene. The aim of this study was to inves
tigate the effects of recombinant human IGF-I (rhIGF-I) therapy on the GH-I
GF system of this patient to gain further insights into its growth-promotin
g and metabolic actions. To assess the changes in GH, IGFs, IGF-binding pro
teins (IGFBPs), acid-labile subunit (ALS), and insulin levels, blood sample
s were obtained before therapy and during the first year of treatment. Horm
ones were analyzed by specific RLAs. Overnight GH profiles were performed b
efore and at 1, 6, and 12 months of therapy. Fasting ALS, IGF-II, IGFBP-3,
IGFBP-2, IGFBP-1, and insulin levels before rhIGF-I treatment were 46.3 mg/
L, 1044 mu g/L, 5.8 mg/L, 73 ng/mL, 4.7 ng/mL, and 27.3 mU/L, respectively
IGF-II, ALS, and insulin levels were elevated, whereas IGFBP-1 and IGFBP-2
levels were decreased compared to reference values. Twenty-four hours after
a single sc injection of rhIGF-I (40 mu g/kg), the concentrations were 46
mg/L, 888 mu g/L, 6.9 mg/L, 112 ng/mL, 5.0 ng/mL, and 21.0 mU/L, respective
ly. After a single sc injection of rhIGF-I of 40 or 80 mu g/kg.day and mode
lling the data using a two-compartment model, the half-lives of elimination
were 15.7 and 14.3 h, with a maximum increase in IGF-I levels to 341 and 7
94 mu g/L around 7 h, respectively. An increase in IGFBP-3 levels was obser
ved with both doses of rhIGF-I, with a peak values of 9 mg/L. GH profiles s
howed a decrease in peak amplitude from 342 to 84 mU/L at 1 month, to 67 mU
/L at 6 months, and to 40 mU/L at 1 yr of therapy, with no significant chan
ges in peak number. A significant increase in IGFBP-1 levels was observed d
uring treatment with 80 mu g/kg.day IGF-I, reflecting the inhibitory effect
of rhIGF-I on insulin secretion. The clinical response to rhIGF-I therapy
was an increased height velocity from 3.8 cm/yr before treatment to 6.6 cm/
yr. Increased lean body mass correlated with changes in the doses of rhIGF-
I and, in turn, with the biochemical changes in the GH-IGF axis. Similar to
healthy individuals, this patient had normal IGFBP-3 and ALS levels, which
are the major regulators of the pharmacokinetics of rhIGF-I. In summary, r
hIGF-I treatment has improved linear growth and insulin sensitivity in this
patient by restoring IGF-I levels and by normalizing circulating GH, IGFBP
, and insulin levels.