Endocrine Abstracts (2001) 2 P33

NORMALISATION OF 150 kDa INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 3 TERNARY COMPLEX FORMATION DURING PEGVISOMANT THERAPY IN ACROMEGALY

C Parkinson1, A Flyvbjerg2 & PJ Trainer1


1Department of Endocrinology, Christie Hospital, Manchester, UK; 2Medical Department M (Diabetes and Endocrinology) Aarhus University Hospital, DK-8000 Aarhus C, Denmark.


Serum IGF-I is increasingly used, and IGFBP-3 has been proposed, as a marker of treatment efficacy in patients with acromegaly. IGF-I bioactivity and half-life are dependent on the degree of IGF-I incorporation into 150kDa ternary complexes with IGFBP-3 and ALS. When serum GH is lowered in patients with acromegaly all three ternary complex components decline, but effects on ternary complex formation have not been described. We investigated GH action on ternary complex formation using sera from 16 patients (9 male, median age 57 [range 27-78]) with active acromegaly (serum IGF-I >30% upper limit of age-related reference range) who normalised serum IGF-I during pegvisomant therapy (dose 15mg (5-40)) and 8 sex/age-matched controls. Serum IGF-I, IGFBP-3 proteolysis and total, non-bound (45kDa), and ternary complex associated IGFBP-3 were measured (single batch) on fasting samples from baseline and following IGF-I normalisation, by RIA (IGF-I [Nichols]) and IRMA (IGFBP-3 [DSL]). IGFBP-3 profile was determined by Western ligand blot with quantification of IGFBP-3 by IRMA [DSL]. In vivo IGFBP-3 proteolysis was calculated from Western immunoblot as the fragmented IGFBP-3/sum all IGFBP-3 ratio. Compared to controls total and ternary complex associated IGFBP-3 (but not 45kDa IGFBP-3 or proteolysis) were significantly greater in patients at baseline ((mean plus/minus SD) 3962plus/minus751, 3042plus/minus421 micrograms/l, P<0.01). Serum IGF-I normalisation (699plus/minus304 to 242plus/minus112 micrograms/l, P=<0.0001) was associated with a fall in total IGFBP-3 (4345plus/minus752 to 3372plus/minus553 micrograms/l, P=0.0002) due to normalisation of 150kDa IGFBP-3 (3962plus/minus751 to 3008plus/minus543 micrograms/l, P=0.0002). 45kDa IGFBP-3 and IGFBP-3 proteolysis were unaffected (326plus/minus52 to 330plus/minus71 micrograms/l, P=0.86; 30plus/minus14 to 30plus/minus15%, P=0.75 respectively). In conclusion, GH receptor blockade in patients with acromegaly, lowers all components of the ternary complex and ternary complex formation. These data demonstrate ternary complex formation, not IGFBP-3 proteolysis, is GH dependent and that measurement of ternary complex associated IGFBP-3 in patients with acromegaly may provide useful information regarding disease activity.

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