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2 Division of Experimental Therapy, 3 Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; 4 Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands; 5 Department of Clinical Chemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands; 6 Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, Utrecht, The Netherlands; 7 Fred Hutchinson Cancer Research Center, Seattle, Washington; 8 Department of Gastroenterology and Hepatology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; 9 Department of Gastroenterology, Gelderse Vallei Hospital, Ede, The Netherlands; and 10 Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: m.rookus{at}nki.nl.
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ABSTRACT |
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 TOP ABSTRACT IntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Estrogenic substances, such as oral estrogen replacement therapy (OERT), are associated with decreased colon cancer risk (5). Both OERT (6,7) and selective estrogen receptor modulators (SERM) (8–10) reduce serum IGF-I concentrations. Isoflavones are a class of phytoestrogens mainly present in soy products and extensively studied for their potential anticarcinogenic effects (11). Isoflavones structurally resemble estrogens and possess weak estrogenic activity (12). Therefore, these compounds may induce an estrogen-like reduction of IGF-I in the circulation.
In vitro and in vivo animal studies indicate that (soy) isoflavones may decrease serum IGF-I concentrations, whereas cross-sectional studies in humans did not find clear associations between soy isoflavone intake and serum IGF-I concentrations (4). Several randomized controlled supplementation studies of soy protein isolates containing isoflavones in humans found either no effect (13–15) or an increase (16–20) in serum IGF-I concentrations by soy isoflavones. The inconsistency in these results may be explained by potential IGF-increasing effects of soy protein itself, which can mask a potentially IGF-lowering effect of isoflavones alone (4).
Isolated isoflavones can be derived from red clover, which has a different isoflavone composition, but may result in a similar isoflavone blood profile compared with soy products (21). To our knowledge, red clover isoflavones have not been previously studied for their IGF effects in men or in relation to the risk of colorectal cancer. Therefore, we investigated the effect of a 2-mo isolated red clover isoflavone supplementation (84 mg/d) on serum concentrations of IGF and various IGFBP in a male population at increased risk of colorectal cancer that could potentially benefit most from this intervention. Because the biological effectiveness of isoflavones may depend on the individual ability to biotransform isoflavone metabolites to the more potent estrogenic metabolite equol (22), we also evaluated whether effects of isoflavones on circulating IGF were related to the ability to produce equol.
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Materials and Methods |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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The study was conducted in 4 hospitals in the Netherlands: the Antoni van Leeuwenhoek Hospital in Amsterdam, the Gelderse Vallei Hospital in Ede, the Slotervaart Hospital in Amsterdam, and the Sint Antonius Hospital in Nieuwegein. The study protocol was approved by the Medical-Ethical Committees of all participating centers.
Design.
We conducted a randomized, placebo-controlled, double-blind crossover study. The total duration of the study was 
6 mo, consisting of two 8-wk intervention periods separated by an 8-wk washout period. Surveillance colonoscopies in study participants were always planned at the end of the 1st intervention period. Subjects were allocated to receive isoflavone tablets in the 1st intervention period and placebo tablets in the 2nd [isoflavones-placebo (IP group)] or vice versa [placebo-isoflavones (PI group)], according to a randomization scheme with permuted blocks. The isoflavone tablets (Promensil, Novogen) contained an isoflavone extract derived from red clover containing 42 mg of total isoflavones (25 mg biochanin, 8 mg formononetin, 4 mg genistein, and 5 mg daidzein). Subjects were asked to take 2 tablets/d, one with breakfast and one with dinner (total dose, 84 mg/d). Subjects were asked to maintain their habitual diet and lifestyle.
Data collection. Subjects visited the hospital at the beginning and end of both intervention periods. At each visit, blood samples were drawn after an overnight fast, and weight, waist, and hip circumference were measured. To assess habitual diet of the study population, a 24-h recall was conducted at each study visit. The method of interviewing and coding of foods and portion sizes was standardized and was performed by trained nutritionists and graduate students in nutrition. Energy and nutrient intakes were calculated using the VBS food calculating system (BAS Nutrition Software) based on the Dutch food composition table (23). Habitual physical activity over the 2 mo preceding each visit was assessed using the validated self-administered Short Questionnaire to Assess Health-enhancing physical activity (SQUASH) (24). During both intervention periods, subjects kept a daily notebook in which they recorded information about their health, medicine use, smoking, and consumption frequency of products rich in isoflavones (i.e., soy products, legumes, and nuts). Compliance was measured by counting returned tablets, self-reported supplement intakes from daily notebooks, and serum genistein concentrations at the beginning and end of both intervention periods.
Laboratory analyses. Fasting serum and EDTA-plasma samples were frozen and stored at –30°C until further analysis. All IGF-system components were measured at the end of both intervention periods. Serum total IGF-I was measured using an immunometric technique on the Advantage Chemiluminescense System (Nichols Institute Diagnostics). The sensitivity was 6.0 µg/L, intra-assay CV were 8.0% and 6.0% (n = 25) at 30 and 450 µg/L mean serum IGF-I, and interassay CV were 8.7%, 5.8% and 6.5% (n = 115) at 33, 174, and 445 µg/L mean serum IGF-I, respectively. Plasma free /IGFBP dissociable IGF-I was measured using a highly sensitive 2-site immunoradiometric free IGF-I kit (Diagnostic Systems Laboratories). The sensitivity was 0.2 µg/L, and the interassay CV was 12% at a mean plasma free IGF-I concentration of 1.6 µg/L. Serum IGF-II concentrations were determined in Sep-Pak C18 extracts of serum by RIA, as described previously (25,26). The sensitivity was 0.09 µg/L and intra- and interassay CV were 6.7 and 8.8% (n = 12) at 505 µg/L mean serum IGF-II, respectively. Serum IGFBP-1, IGFBP-2, and IGFBP-3 were determined by specific RIA. Relevant technical details were described previously (25,27,28). Total IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3 assays were performed in the same laboratory.
Serum genistein was measured at all 4 time points using reversed phase HPLC with UV detection according to methods adapted from Supko et al. (29) and Busby et al. (30). The sensitivity was 37 nmol/L, and the accuracy and precision were within 100 ± 15% and 15%, respectively.
Serum equol concentrations were measured in samples collected after isoflavone intervention. TR-FIA kits (Labmaster) were used as described previously (31) and fluorescence was measured with a Victor 2 model 1420 spectrofluorometer (Wallac). The sensitivity was 3.3 nmol/L and intra-assay CV was 12.3% at a mean equol concentration of 134 nmol/L.
Statistical analyses.
The parameter of interest in our statistical analysis was the relative crossover difference (see formulas below), expressed as a percentage relative to the concentration after placebo. The mean crossover difference for each IGF system component was calculated for both intervention groups (IP and PI) and then pooled over the 2 intervention groups, to adjust for period effects. We tested whether the pooled crossover difference significantly deviated from null with a t test (2-sided 
= 0.05, df = 37) using the pooled SEM crossover differences (32).
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Descriptive characteristics were computed for both randomized groups separately. We calculated whether relevant changes occurred in dietary and lifestyle factors that are known to influence the IGF-system (i.e., dietary intake of macronutrients, weight, waist, and hip circumference, total physical activity score, and dietary intake of products relatively rich in isoflavones) during the study period for both intervention groups separately. To evaluate whether the relative crossover differences correlated with serum genistein and equol concentrations after isoflavone supplementation, Spearman correlation coefficients were calculated. Logarithmic curve estimation was performed to obtain Figure 1.
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Results |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Men in the IP group were slightly heavier, had a greater BMI and waist circumference, and were more often nonsmokers than those in the PI group (Table 1). The number of participants with a family history of colorectal cancer and/or a personal history of colorectal adenomas was equally distributed over the 2 groups.
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80% of tablets taken). For 29 of 37 men (78%), mean serum genistein concentrations after isoflavone intervention (252 ± 252 nmol/L; range 46 to 1274 nmol/L) had increased compared with all other time points (generally below detection limit of 37 nmol/L). Body weight, waist, and hip circumference, total physical activity score, dietary macronutrient intake, and the number of days that products rich in isoflavones were consumed did not materially differ for the isoflavone vs. the placebo intervention period (data not shown).
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Discussion |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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To our knowledge, this is the first randomized controlled trial that correlates the effects of isolated isoflavones with both serum IGF-I and equol status in men. We used a crossover design, which has the important advantage of obtaining results unaffected by the high interindividual variation in circulating IGF-concentrations relative to the much lower intraindividual variation. Our study population consisted of men at high-risk for colorectal cancer who could potentially benefit most from this isoflavone intervention. The number of recruited individuals for our study was more than sufficient, and the dropout rate was low (5%) and unrelated to supplement intake, which resulted in an adequately powered study. Compliance was high (95%) and genistein concentrations were increased in 78% of the participants. Blinding was confirmed by the fact that only 22% of the participants correctly guessed the period in which they received the isoflavone supplements. Furthermore, factors thought to potentially influence circulating concentrations of IGF and IGFBP did not materially change during the study; therefore, changes in various parameters of the IGF-system could mainly be attributed to the isoflavone intervention.
To our knowledge, only 1 pilot crossover study investigated the effect of an isolated red clover isoflavone supplementation on the IGF-system in humans. This study did not observe any effects on serum IGF-I and IGFBP-3 after 1 mo in both pre- and postmenopausal women (33), which is in line with our results in men. The 2-mo duration of isoflavone supplementation in our study was likely sufficient to affect the circulating IGF-system, insofar as human intervention studies on oral estrogens and SERM also observed a decrease in serum IGF-I after 2 mo (6,8). The differential effects on IGF for isoflavones compared with that of estrogens and SERM may be explained by their much weaker estrogenic activity (34). However, serum genistein concentrations in subjects with high soy consumption can far exceed those of endogenous estrogens, reaching levels sufficient to produce relevant biological effects (12).
The biological effects of isoflavones may also depend on the source and metabolism of isoflavones. In previous randomized controlled studies, the separate effects of isoflavones, soy protein, and calcium on the circulating IGF-system were difficult to disentangle (4). Therefore, we investigated a source of isolated isoflavones using a red clover supplement. Red clover isoflavones mainly consist of biochanin A and formononetin, which are metabolized to genistein and daidzein, respectively. Soy mainly contains the glucoside isoflavones genistin and daidzin, which are also metabolized to genistein and daidzein in the intestines (34). Differences in composition between soy and red clover have been shown not to affect bioavailability within individuals (35). Plasma genistein and daidzein concentrations after red clover isoflavone supplementation are within the range of plasma concentrations in subjects who traditionally consume a high-isoflavone soy-based diet (50–800 µg/L) (21). The bioavailability of isoflavones, however, may vary up to 10-fold between individuals (35). We also encountered large interindividual differences in serum genistein concentrations after isoflavone intervention. However, the relative difference in serum IGF-I concentrations after isoflavones and placebo did not correlate with serum genistein concentrations.
Recently, it has been hypothesized that only equol producers may benefit from isoflavone consumption (22). Approximately 30–50% of individuals are able to convert daidzein, one of the main isoflavone metabolites, to the more potent estrogenic isoflavone equol (36). Mice and rats metabolize the majority of daidzein to equol (22), and their serum IGF-I concentrations decreased with physiological dietary intakes of soy or genistein (37,38). Accordingly, the majority of equol producers in our study had decreased IGF-I concentrations after consuming isoflavones compared with placebo. IGF-I concentrations after placebo did not differ between equol producers and nonproducers, suggesting that equol production, rather than host factors associated with equol production, may be important with respect to IGF modulation (36).
In conclusion, isolated isoflavones did not influence serum IGF-I concentrations in our adequately powered, randomized, placebo-controlled, double-blind crossover trial in a male population at increased risk of colorectal cancer. These results suggest that the increased serum IGF-I concentrations observed in previous studies investigating soy food or soy protein supplementation are most likely due to soy protein, and not to isoflavones. Although based on small numbers of equol producers, our data suggest that isoflavones might have an IGF-lowering effect in equol producers only. Therefore, it is important that our results are confirmed in larger human-intervention studies among men and women using isolated isoflavones and giving consideration to equol status.
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FOOTNOTES |
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11 Abbreviations used: IGF, insulin-like growth factor(s); IGFBP, IGF binding protein(s); IP, isoflavones-placebo; PI, placebo-isoflavones; SERM, selective estrogen receptor modulator(s).
Manuscript received 23 August 2006. Initial review completed 24 September 2006. Revision accepted 30 November 2006.
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LITERATURE CITED |
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40 nmol/L were previously defined as equol nonproducers (