Intentional weight loss may reduce breast cancer risk through lowering levels of circulating free IGF-I but few studies have measured this longitudinally. We determined the effect of weight loss (=5% body weight) over 12 months, using an energy restriction and exercise programme, on an expanded panel of IGF-related peptides amongst 23 weight losing and 46 weight stable or gaining pre-menopausal women at increased risk of breast cancer, BMI (mean ± SD) 29.2 ± 6.2 kg/m2. Fasting measures of total and free IGF-I (ultra-filtration), and IGFBP-1, -2 and -3, body weight, body fat (DXA), intra-abdominal fat (MRI) were assessed at 6 and 12 months.\ud \ud After 12 months, women who lost ≥ 5% of body weight had a significant increase in serum total IGF-I; mean (95% CI difference) 17 (2.3 to 34.0) μg/l, P < 0.05, and IGFBP-2; mean (95% CI ratio) 1.24 (1.06 to 1.46) P < 0.001, compared to weight stable/gaining women. Serum IGFBP-1 tended to increase in weight losers compared to the weight stable/gaining women; mean (95% CI ratio) 1.19 (0.97 to 1.45) P=0.09, whereas IGFBP-3 remained unchanged; mean (95% CI ratio) 1.02 (0.94 to 1.20] P=0.99. Weight loss did not significantly alter serum levels of free IGF-I; mean difference 0.1 (-0.1 to 3.4) μg/l, P=0.21.\ud \ud Increased serum total IGF-I levels, and maintenance of free IGF-I despite increased concentrations of serum IGFBP-1 and -2 with weight loss, does not suggest intentional weight loss with diet and exercise mediates reduced risk through the circulating IGF-axis
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