Affiliations of authors: R. Kaaks, International Agency for Research on Cancer, Lyon, France; S. Söderberg, T. Olsson, G. Hallmans (Department of Public Health and Clinical Medicine), P. Stattin (Department of Urology and Andrology), Umeå University Hospital, Sweden.
Correspondence to: Pär Stattin, M.D., Ph.D., Department of Urology and Andrology, Umeå University Hospital, 901 85 Umeå, Sweden (e-mail: par.stattin{at}urologi.umu.se).
Drs. Allen and Key present evidence that suggests a relationship between serum IGF-I concentrations and diets rich in animal protein and associated essential amino acids. This very interesting observation is in line with results from several intervention studies in humans that showed that the intake level of protein, and especially of essential amino acids, is a key determinant of circulating IGF-I levels (1,2). We share the view of Drs. Allen and Key that an elevated intake of animal protein might, at least partly, explain the high incidence rates of prostate cancer in westernized, industrial countries.
A parallel hypothesis is that the balance between energy intake and expenditure also affects circulating IGF-I levels, which in turn affect prostate cancer risk. However, the relationship between plasma levels of IGF-I, prostate cancer, and adiposity (as a result of high energy intake and low expenditure) is complex. Results from a large number of epidemiologic studies [reviewed in (3)] have shown no consistent relationship between prostate cancer risk and body mass index (BMI). Furthermore, cross-sectional studies [reviewed in (4)], mostly in well-nourished Western populations, have also not shown a simple, direct relationship between BMI and circulating levels of IGF-I. On the contrary, a comparatively elevated BMI (>30 kg/m2) is associated with decreased, rather than increased, levels of IGF-I (4). Nevertheless, we would not rule out the existence of a positive association between IGF-I and adiposity in populations where the majority of subjects have a BMI below 2224 kg/m2, as is the case in many developing countries where prostate cancer risk is low. This would imply a nonlinear relationship between adiposity and IGF-I levels, with peak levels of IGF-I occurring in individuals with a BMI of about 25 kg/m2, and a gradual decrease at higher levels of adiposity. This hypothesisthat increasing IGF-I levels accompany increasing adiposity in nonobese individualsfits with observations made in patients with anorexia nervosa and also fits with observations that only a minimum level of endogenous insulin is required for tissues to respond optimally to growth hormone, the principal stimulus for IGF-I synthesis (5,6). In contrast, obesity and chronic hyperinsulinemia decrease pituitary growth hormone secretion and, hence, cause a drop in the level of IGF-I (3).
Recent analyses in our Umeå cohort give some additional support to the hypothesis of a nonlinear relationship between IGF-I concentrations and adiposity. Although there was no significant linear correlation (r = .03) between BMI and IGF-I levels, we did observe a slight increase in IGF-I levels from the first to the third quintile of BMI as well as a slight decrease in IGF-I levels from the third to the fifth quintile of BMI (Table 1). We also analyzed the relationship between levels of IGF-I and of leptin, a molecule that may reflect adiposity more directly than BMI, and found a similar nonlinear association between levels of IGF-I and leptin both in men (Table 1
) and in women (data not shown). It is interesting that we also observed a statistically significant increase in prostate cancer risk for the second and third quintiles of leptin concentration (7), although BMI was unassociated with prostate cancer risk.
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REFERENCES
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4 Kaaks R, Lukanova A. Energy balance and cancer: the role of insulin and insulin-like growth factor-I. Proc Nutr Soc. In press 2001.
5 Counts DR, Gwirtsman H, Carlsson LM, Lesem M, Cutler GB. The effect of anorexia nervosa and refeeding on growth hormone-binding protein, the insulin-like growth factors (IGFs), and the IGF-binding proteins. J Clin Endocrinol Metab 1992;75:7627.[Abstract]
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7 Stattin P, Soderberg S, Hallmans G, Bylund A, Kaaks R, Stenman UH, et al. Leptin is associated with increased prostate cancer risk: a nested casereferent study. J Clin Endocrinol Metab. In press 2001.
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