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Human Nutrition and Metabolism
Research Communication

Soy Isoflavones Do Not Modulate Circulating Insulin-Like Growth Factor Concentrations in an Older Population in an Intervention Trial

Kenneth F. Adams^*,, Katherine M. Newton^,**, Chu Chen^*,, Scott S. Emerson^*, John D. Potter^*,, Emily White^*, and Johanna W. Lampe^*,,**,3

^* Fred Hutchinson Cancer Research Center, University of Washington, and ^** Center for Health Studies, Group Health Cooperative, Seattle, WA

³To whom correspondence should be addressed. E-mail: jlampe{at}fhcrc.org.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Insulin-like growth factors (IGF) are essential for normal growth and maintenance of lean muscle mass; however, high insulin-like growth factor-I (IGF-I) and low IGF binding protein-3 (IGFBP-3) levels are also associated with several cancers. To test the hypothesis that long-term soy isoflavone supplementation decreases circulating IGF-I concentrations, we conducted a controlled, parallel-arm, double-blind intervention study with 150 participants (85% men), 50–80 y old. Participants were randomly assigned to consume a soy beverage powder daily for 12 mo. The active treatment group (+ISO) received soy protein containing 83 mg isoflavones, whereas the comparison group (-ISO) received soy protein containing 3 mg isoflavones. Serum IGF-I and IGFBP-3 were measured by ELISA. Mean change in serum IGF-I concentrations was similar in the two groups (+1.4 nmol/L in +ISO, +1.2 nmol/L in -ISO; P = 0.74, 95% confidence interval -1.1, +1.5 nmol/L for the 0.21 nmol/L difference between groups), indicating no effect of the isoflavone intervention. Similarly, the changes in IGFBP-3 and the IGF-I/IGFBP-3 ratio were similar in both groups, again showing no effect of +ISO treatment. A 12 mo, 83 mg/d soy isoflavone intervention did not modulate serum IGF in an older, mostly male population.

KEY WORDS: • isoflavones • insulin-like growth factor (IGF) • randomized controlled trial

Soy isoflavones, which have weak estrogenic properties, may have chemopreventive effects against colon cancer. Estrogen is protective against colon cancer (1 ,2 ), and because men and postmenopausal women have low levels of circulating estrogen, soy isoflavones are hypothesized to have beneficial effects against colon cancer in these populations.

Insulin-like growth factors (IGF) are circulating peptide hormones and paracrine-signaling molecules that regulate cell proliferation and apoptosis (3 ). Although IGF are necessary for normal growth and maintenance of muscle mass, evidence has accumulated that they play a role in the development of several cancers. High circulating insulin-like growth factor-1 (IGF-I) concentrations, low insulin-like growth factor binding protein-3 (IGFBP-3) concentrations and a high ratio of IGF-I to IGFBP-3 have been associated with prostate, colorectal and premenopausal breast cancer (4 ,5 ).

Circulating IGF levels can be modified, and such modification could potentially affect cancer incidence. Estrogen decreases circulating levels of IGF (6 ), as do the selective estrogen receptor modulators (SERM) tamoxifen and raloxifine (7 –9 ). Animal studies suggest that the beneficial effects of energy restriction on cancer incidence are mediated by reductions in circulating IGF-I (10 ). In a mouse model, a diet high in soy isoflavones led to reduced serum IGF-I levels (11 ). Two small intervention studies in humans found that soy protein increased IGF-I concentration (12 ,13 ), but did not resolve whether isoflavones themselves affected IGF levels.

We sought to determine the effects of isoflavones or other alcohol-soluble components of soy protein on serum IGF-I and IGFBP-3 levels in a larger, long-term intervention in a study population at risk for colon cancer. Given that circulating IGF-I concentrations can be lowered by estrogen, tamoxifen and raloxifine, and that isoflavones reduced serum IGF-I in a mouse model, we hypothesized that soy protein supplementation for 12 mo would decrease circulating IGF-I concentrations, increase IGFBP-3 concentrations and decrease the IGF-I/IGFBP-3 molar ratio.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Subjects.

Participants were recruited from a patient population undergoing colonoscopy in two gastroenterology clinics at Group Health Cooperative, a large managed-care organization in western Washington. Patients were eligible if they were men or women between 50 and 80 y old, with adenomatous colorectal polyps found on current or recent (within 12 mo) colonoscopy, and not taking hormone replacement therapy. Exclusions included various gastrointestinal and other medical conditions and habitual soy food intake 4 servings/wk. Initially, participants were excluded for regular nonsteroidal anti-inflammatory drug (NSAID) use. After y 1 of the study, to increase enrollment, this exclusion was lifted. The study activities were approved by the Institutional Review Boards of the Fred Hutchinson Cancer Research Center, Seattle, WA and Group Health Cooperative, Seattle, WA, and informed, written consent was obtained from all study participants.

Recruitment and intervention.

Participants were recruited in a two-phase process. In the first phase, all age-eligible health plan enrollees scheduled for colonoscopy were contacted by phone in advance of their clinic visit. On the procedure day, consent was obtained to have biopsies collected if adenomatous polyps were found. Of 4085 patients contacted by phone, 1513 were eligible and 749 consented to biopsy. Adenomatous polyps were found in 228 patients; they were asked to participate in the dietary intervention and 177 consented. A 1-wk run-in period was conducted, using a soy drink with isoflavones removed, to determine tolerance for the drink; 150 subjects were enrolled in the study and were randomly allocated to one of the two treatment groups.

Participants were recruited from January 1998 to March 2001. Randomization schedules were stratified by sex and clinic, using block sizes of 4 and 8 individuals, randomly mixed. From January 1999 forward, within strata defined by clinic and sex, participants were also randomly allocated according to NSAID use. Due to a high proportion of women taking replacement estrogen and therefore ineligible, the majority of participants (85%) were men.

Participants were provided a supply of soy drink powder packets (DuPont Protein Technologies, St. Louis, MO) labeled "A" or "B" depending on the outcome of randomization, and asked to consume two packets (total 58 g/d) daily for 12 mo. The daily isoflavone dose of the soy drink in the active intervention (+ISO) was 45.6 mg genistein, 31.7 mg daidzein and 5.5 mg glycitein. The soy drink in the control condition (-ISO) was an ethanol-extract of +ISO and the daily isoflavone dose of -ISO was 1.7 mg genistein, 1.0 mg daidzein and <0.1 mg glycitein. Both soy drinks provided 40 g protein, 836 kJ and 1400 mg calcium/d. The participants were given extensive instruction on ways to incorporate the supplement into their usual dietary pattern, substituting for other foods in the diet. Participants, investigators and staff having participant contact were blinded to the participants’ isoflavone treatment.

Measurements.

Baseline nutrient intakes were measured with a 122-item food-frequency questionnaire (14 ) and soy intakes were determined using a 15-item soy food questionnaire (15 ). Clinic study staff collected blood samples from fasting subjects and weighed participants at the baseline, 4-, 8- and 12-mo clinic visits. Most clinic visits took place during the morning; 87% of serum samples were collected between 0700 and 1200 h. Samples were processed and sera were stored at -70°C until analysis. Participants who consumed 80% of soy packets over the 12-mo intervention, based on a count of packets returned during clinic visits, were considered adherent.

IGF-I and IGFBP-3.

Serum samples were assayed for IGF-I and IGFBP-3 using commercial ELISA kits (Diagnostic Systems Laboratories, Webster, TX). Samples were analyzed in duplicate and were reanalyzed if duplicate CV were >10%. To minimize effects of plate or position on plate, each individual’s samples were run on the same plate strip, with order randomized. Each plate contained a similar number of samples from the intervention and placebo conditions. All samples were analyzed from single IGF-I and IGFBP-3 kit lots. The intrarun CV for the quality control serum samples were: IGF-I, 4.7% (23.3 nmol/L) and IGFBP-3, 3.7% (89.8 nmol/L). The interrun CV were IGF-I, 7.2% and IGFBP-3, 5.8%.

Serum isoflavones.

We measured genistein and daidzein in serum samples using a modified version of the gas chromatography-mass spectrometric method of Adlercreutz et al. (16 ). We added 50 µL of 4-methylumbelliferone glucuronide (50 mg/L) and 40 µL of deuterated internal standards of the unconjugated compounds (10 mg/L; provided by Dr. Kristiina Wähälä, University of Helsinki, Finland) to each 1.0-mL serum aliquot. Trimethyl-silyl derivatives of the samples were analyzed on a Hewlett-Packard 6890 Series gas chromatograph coupled with a 5973 Mass Selective Detector (Agilent Technologies, Palo Alto, CA) in the selected ion monitoring mode. A quality control serum sample was included in duplicate in each run. The intrarun CV for the quality control serum samples were daidzein, 5.3% (837 nmol/L) and genistein, 6.4% (1461 nmol/L). The interrun CV were daidzein, 15.6% and genistein, 18.8%.

Statistical analysis.

The statistical analysis was a comparison of mean change in serum IGF-I concentrations between +ISO and -ISO groups after a 12-mo intervention, using a linear regression model with robust standard error estimates to account for unequal variances. Similar comparisons were made for IGFBP-3 and the molar ratio of IGF-I to IGFBP-3. The primary analysis was by intention to treat, based on comparisons between groups as defined at randomization. We adjusted for baseline levels of the response variable and stratification variables (clinic, sex and NSAID use). Baseline vs. 12-mo comparisons of IGF measurements, with treatment groups combined, were made using a paired t test. Analyses were carried out using Stata (version 7.0; Stata Corporation, College Station, TX) statistical software. An -level of 0.05 was used.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Baseline characteristics of participants in the isoflavone intervention (+ISO, n = 74) and comparison (-ISO, n = 76) groups did not differ (Table 1). At the 12-mo clinic visit, 58 participants remained in the +ISO group and 65 in the -ISO group. Sixteen participants dropped out of the +ISO group; reasons obtained from 14 subjects included 7 health- and 7 nonhealth-related (e.g., logistical) reasons. Eleven participants dropped out of the -ISO group; reasons obtained from 9 subjects included 6 health- and 3 nonhealth-related reasons. Of the participants randomized, 46 (62.2%) in the +ISO group adhered to treatment assignment (80% packets consumed), compared with 58 (76.3%) in the -ISO group (P = 0.06). Of the participants who completed the study (i.e., returned for the 12-mo follow-up visit), 46 (79.3%) in the +ISO group adhered to treatment assignment and 58 (89.2%) in the -ISO group adhered (P = 0.13). Isoflavone concentrations were not significantly different in the two groups at baseline, and were significantly higher in the +ISO group than in the -ISO group at 4, 8 and 12 mo (Table 2). Mean body weight did not change between baseline and 12 mo [mean change + 0.062 kg; 95% CI -0.54, +0.66 kg; P = 0.8).

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
This study shows that soy isoflavone supplementation at a dose of 83 mg/d for 12 mo does not alter serum IGF concentrations in an older, predominantly male, population. IGF-I can be modulated by exogenous estrogen, SERM and diet, as shown by several intervention studies. Exogenous estrogen decreases circulating IGF-I (6 ,17 ). The SERM tamoxifen and raloxifene, which have partial estrogen agonist/estrogen antagonist activities, also decrease circulating IGF-I concentrations (7 –9 ,17 ,18 ). Consistent with its role as a regulator of growth, circulating IGF-I increases with greater energy (19 ) or protein intake (20 ), and decreases with energy or protein restriction (21 ). In a mouse prostate cancer model, a diet of soy protein isolate fortified with high levels of extracted isoflavones reduced serum IGF-I; it also reduced tumor cell proliferation, increased apoptosis and decreased angiogenesis (11 ). Due to the ability of isoflavones to act as estrogens under certain conditions (22 ), their similarities to SERM (23 ) and their ability to reduce serum IGF-I concentrations in a mouse model (11 ), we hypothesized that isoflavones might reduce circulating IGF-I levels, but did not find this to be the case at the dose supplied.

Two recent, small human intervention studies investigated the effects of soy protein containing isoflavones on circulating IGF-I (12 ,13 ). Wangen et al. (12 ) reported higher circulating IGF-I concentrations after intervention with a control diet (supplementation with soy protein containing 7 mg isoflavones/d) compared with baseline (habitual) diet, in a study of postmenopausal women. They also reported lower IGF-I concentrations at the highest isoflavone dose assigned (132 mg/d) compared with the low isoflavone (65 mg/d) control diet. These findings suggest that soy protein itself increases serum IGF-I levels, whereas the isoflavone component of the protein powder has the opposite effect. Khalil et al. (13 ) reported that supplementation with 40 g/d soy protein containing isoflavones (88 mg/d) for 3 mo increased serum IGF-I concentrations in men (27–84 y), compared with milk protein. Because the control group in that study received milk-based protein, it was not resolved whether the effect of the soy protein supplement on IGF-I could be attributed to isoflavones, soy protein itself or some other component. Our study, which found no difference in IGF-I concentration between the intact soy protein (+ISO) and alcohol-washed soy protein (-ISO) groups, suggests that the increase in serum IGF-I found by Khalil et al. (13 ), feeding intact soy protein, was unlikely to be due to the isoflavone, or other alcohol-soluble components of the soy supplement. Furthermore, although we noted increased IGF-I levels in a before-after treatment comparison (not a randomized comparison), the effect was not nearly as large as that reported by Khalil et al. (13 ) at the most comparable time (4 mo). In a recent observational study, IGF concentrations were higher in vegan women who consumed 3/4 pint (426 mL) soy milk/d than those who did not (24 ).

The study had several strengths. We intervened in a population that is at increased risk for colorectal cancer and thus could potentially benefit from the intervention. Our randomized, double-blind design, using an intention to treat analysis, minimized the likelihood of bias or noncausal associations. Our study is the largest to date evaluating the effect of isoflavones on IGF. The 12-mo study duration was long enough to determine whether isoflavones have sustained effects on circulating IGF levels, and intermediate measurements were taken to detect any transient effects.

The study has limitations, but we do not believe they substantially affect our conclusions. Eighteen percent of participants did not complete the study. We conducted a sensitivity analysis to determine whether dropout could have affected our results. This analysis showed that we would have found a significant effect of the +ISO intervention only if the participants who dropped out of the +ISO group had experienced increases in IGF-I concentrations of at least 7 nmol/L or decreases of at least 12 nmol/L (these represent changes of 2 SD), and IGF-I concentrations of dropouts in the -ISO group had not changed. This seems unlikely, given that in the analysis of participants who did complete the study, the differences between groups were very small. An additional 20% of participants did not adhere to the treatment; however, analysis of participants restricted to those who adhered to treatment did not change the results. Another possible explanation for our null findings is that the isoflavone dose we tested was too low to elicit an effect on serum IGF-I concentrations. We chose the dose as one attainable by persons consuming soy foods. We cannot rule out the possibility that isoflavones would have an effect on IGF in a different population (e.g., younger, one with more women). It is also possible that the increase in serum IGF concentration due to soy protein masks an IGF-lowering effect of isoflavones alone.

We found no evidence that soy protein supplementation at 83 mg isoflavones/d reduces circulating IGF-I levels. We did confirm the finding of other recent studies that soy protein intervention increases serum IGF-I; however, we showed that this increase was not due to isoflavones or other alcohol-soluble components of soy protein. The implications of this study are as follows: 1) any cancer chemopreventive effects of soy isoflavones in a population of predominantly older men are unlikely to be due to modulation of serum IGF; and 2) the recently reported increase in circulating IGF-I concentrations after soy protein supplementation is not due to the effects of isoflavones, at least not at the nutritional dose used in this study.

	ACKNOWLEDGMENTS

 
We acknowledge the helpful contributions of Lisa Levy at the Fred Hutchinson Cancer Research Center and Kelly Ehrlich, Linda Palmer and Tina Stroh from Group Health Cooperative.

	FOOTNOTES

 
¹ Presented in part at the American Institute for Research on Cancer International Research Conference on Food, Nutrition, and Cancer, 11–12 July, 2002, Washington, DC [Adams, F., Newton, K. M., Chen, C., Emerson, S. E., Potter, J. D. & Lampe, J. W. (2002) Soy isoflavones do not modulate insulin-like growth factors in an older population: a randomized controlled trial. J. Nutr. 132: 3555S–3556S.

² Supported by National Institutes of Health grants U01 CA72035, R03 CA92772, and T32 ES07262 (support of K.A.).

⁴ Abbreviations used: IGF, insulin-like growth factors; IGF-I, insulin-like growth factor-I; IGFBP-3, insulin-like growth factor binding protein-3; +ISO, 58 g/d soy protein powder supplement containing 83 mg isoflavones; -ISO, 58 g/d soy protein powder supplement containing 3 mg isoflavones; NSAID, nonsteroidal anti-inflammatory drug; SERM, selective estrogen receptor modulators.

Manuscript received 28 November 2002. Initial review completed 8 December 2002. Revision accepted 4 February 2003.

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TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Adams, K. F. Articles by Lampe, J. W. Search for Related Content PubMed PubMed Citation Articles by Adams, K. F. Articles by Lampe, J. W.