High levels of 150-kDa insulin-like growth factor binding protein three ternary complex in patients with acromegaly and the effect of pegvisomant-induced serum IGF-I normalization.
OBJECTIVE
To assess the effect of pegvisomant-induced serum insulin-like growth factor 1 (IGF-1) normalization on IGF binding proteins 1, 2, 3 (IGFBP-1, IGFBP-2 and IGFBP-3), total, non-bound (45 kDa) and 150-kDa ternary complex-associated IGFBP-3, and in vivo IGFBP-3 proteolysis in patients with active acromegaly.


METHODS
The above parameters were measured in 16 patients (median age 57 (range 27-78)) with active acromegaly (serum IGF-I at least 30% above the upper limit of an age-related reference range after washout) in a paired manner on samples obtained after washout and the first occurrence of serum IGF-I normalization during pegvisomant therapy (median dose 15 mg/day (10-40 mg)).


RESULTS
Total IGFBP-3 and 150-kDa ternary complex-associated IGFBP-3 were significantly elevated in patients at baseline compared to controls ((mean+/-SEM) 4345+/-194 vs. 3456+/-159 microg/L, P<0.01 and 3908+/-160 va. 3042+/-149 microg/L, P<0.01, respectively), but no significant difference in 45-kDa IGFBP-3 or in vivo IGFBP-3 proteolysis was observed. Serum IGF-I normalization (699+/-76 to 242+/-28 microg/L, P<0.0001) was associated with a fall in total IGFBP-3 (4345+/-194 to 3283+/-160 microg/L, P<0.001) due to a reduction in 150-kDa ternary complex-associated IGFBP-3 (3908+/-160 to 3008+/-140 microg/L, P<0.0001). 45 kDa IGFBP-3 and in vivo IGFBP-3 proteolysis were unaffected by GH receptor blockade (326+/-13 to 330+/-18 microg/L, P=0.86; 30+/-3.5 to 30+/-3.9%, P=0.75, respectively).


CONCLUSIONS
GH receptor blockade in patients with acromegaly lowers IGF-I and 150-kDa IGFBP-3 ternary complex formation. 50 kDa ternary complex formation (not in vivo IGFBP-3 proteolysis) is GH dependent and measurement of 150-kDa ternary complex-associated IGFBP-3 may provide useful information regarding treatment efficacy in patients with acromegaly.
Parkinson
Craig
C
Department of Diabetes and Endocrinology, The Ipswich Hospital, Heath Road, Ipswich, Suffolk IP4 5PD, UK. craig.parkinson@isph-tr.anglox.nhs.uk
Flyvbjerg
Allan
A
Trainer
Peter J
PJ
D000172:Acromegaly / Q000097:blood / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D005260:Female; D019382:Human Growth Hormone / Q000031:analogs & derivatives / Q000627:therapeutic use*; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood / Q000187:drug effects; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood / Q000187:drug effects; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood* / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D046911:Macromolecular Substances; D008297:Male; D008875:Middle Aged; D012016:Reference Values
D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D046911:Macromolecular Substances; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; C406545:pegvisomant