Hormonal and metabolic effects and pharmacokinetics of recombinant insulin-like growth factor-I in growth hormone receptor deficiency/Laron syndrome.
Profound growth failure despite elevated GH levels in GH receptor deficiency (GHRD) results from reduced insulin-like growth factor-I (IGF-I) synthesis. Recent reports of improved growth velocity in children with GHRD during IGF-I therapy indicate growth-promoting potential in humans. We evaluated the pharmacokinetics and metabolic/hormonal effects of recombinant human IGF-I (40 micrograms/kg every 12 h) given sc for 7 days to six adults with GHRD. Hypoglycemia (< 2.5 mmol/L) did not occur, and mean 2 h postprandial insulin levels were reduced. Urinary calcium increased 2-fold (P < 0.01), and serum calcium was unchanged. The mean integrated 24-h GH level was suppressed (6.5 +/- 2.1 to 1 +/- 0.2 micrograms/L), as were the number of peaks, area under the curve, and clonidine-stimulated GH release (all P < 0.05). The mean pretreatment IGF-I level (36 +/- 2 micrograms/L) was 19% of the Ecuadorian control value (190 +/- 15 micrograms/L), it achieved a peak (253 +/- 11 micrograms/L) between 2-6 h after IGF-I injection, and at 12 h it was 137 +/- 8 micrograms/L. There were no significant changes in the half-life (8.2 +/- 1.5 to 9.7 +/- 1.9 h) or metabolic clearance (0.35 +/- 0.1 to 0.24 +/- 0.05 mL/kg.min) between days 1 and 7; however, distribution volume increased (183 +/- 10 to 266 +/- 36 mL/kg; P < 0.03). Baseline IGF-II levels were 47% of the control value and decreased during IGF-I therapy (273 +/- 10 to 178 +/- 9 micrograms/L; P < 0.01), correlating inversely with IGF-I levels (r = -0.3; P < 0.001). Although IGF-binding protein-3 (IGFBP-3) levels were not significantly influenced, baseline IGFBP-2 levels (153% of the control) increased 45% (P < 0.01). We conclude that IGF-I (40 micrograms/kg every 12 h) given sc to adults with GHRD is safe; achieves normal levels of IGF-I; reduces insulin, IGF-II, and GH levels; and increases IGFBP-2 concentrations and urinary excretion of calcium.
Vaccarello
M A
MA
Department of Pediatrics, Gainesville 32610.
Diamond
F B
FB
Guevara-Aguirre
J
J
Rosenbloom
A L
AL
Fielder
P J
PJ
Gargosky
S
S
Cohen
P
P
Wilson
K
K
Rosenfeld
R G
RG
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000097:blood / Q000652:urine; D002352:Carrier Proteins / Q000097:blood; D003000:Clonidine; D004484:Ecuador; D005260:Female; D013006:Growth Hormone / Q000172:deficiency* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007328:Insulin / Q000097:blood; D018971:Insulin-Like Growth Factor Binding Protein 2; D007334:Insulin-Like Growth Factor I / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D007700:Kinetics; D008297:Male; D011986:Receptors, Somatotropin / Q000502:physiology*; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D013577:Syndrome
D001786:Blood Glucose; D002352:Carrier Proteins; D007328:Insulin; D018971:Insulin-Like Growth Factor Binding Protein 2; D011986:Receptors, Somatotropin; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D013006:Growth Hormone; D003000:Clonidine; D002118:Calcium