Soybean isoflavones: Do the data support a nutrient reference value?

Transcription

1 Soybean isoflavones: Do the data support a nutrient reference value? Mark Messina, PhD November 1, 2013 markjohnmessina@gmail.com

2 Soybean isoflavones: Do the data support a nutrient reference value? Isoflavone intake Isoflavone basics Hot flashes CVD Safety Recommendations

3 Adequate Intake (AI): Recommended average daily intake level based on estimates of nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate in nutrition status.

4 Food Isoflavone Content Present only in minute amounts in most foods Only soyfoods provide nutritionally relevant amounts Traditional soyfoods: ~25 mg/serving ~3.5 mg/g protein

5 Western Isoflavone Intake <3 mg/day Bai et al. Int J Food Sci Nutr 2013 Br J Nutr 2003;89 Suppl 1:S ;

6 Asian Isoflavone Intake How much? In what form?

7 Sources and amounts of isoflavones consumed varies widely among Asian populations

8 Traditional Asian Soyfoods Unfermented Fermented Edamame Tofu Miso Natto Soymilk Tempeh

9 Glc OH O 7 7 Genistin A Genistein A 5 5 OH OH O C O O C O B B Glucosyl-7-genistein 5,7,4'-Trihydroxyisoflavone OH Pharmacokinetic differences? OH Glycoside Form in soybeans and unfermented soyfoods Aglycone Present in varying amounts in fermented soyfoods

10 Mean Asian Isoflavone Intake Location mg/d Type of soyfood Shanghai Unfermented Japan % unfermented Korea % unfermented Singapore Unfermented Hong Kong Unfermented

11 Mean Asian Isoflavone Intake Location mg/d Type of soyfood Shanghai Unfermented Japan % unfermented Korea % unfermented Singapore Unfermented Hong Kong Unfermented

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13 Food Intake (g/d) in Different Chinese Provinces JN YZ GZ CD Rice Wheat Eggs Soy JN Sichuan Province; YZ Shandong Province; GZ Guangdong Province; CD Jiangsu Province. N=540 Males. FFQ, Public Health Nutr 5: 829, 2002

14 Mean Isoflavone Intake 1 among 45,694 Middle-Aged 2 Women from Shanghai Soy protein intake groups (n) 4,007 23,273 12,859 4, (n)% mg/d Mean intake, 40.8 ± 28.7 AJCN 2005;81: Validated FFQ. 2 Mean age, 49.9 ± 8.5

15 Mean Isoflavone Intake 1 among 15,607 Middle-Aged 2 Japanese Women Soyfood intake quartiles Age (n) mg/d ± 10.0; 33.9 ± 7.8; 44.7 ± 10.1; 67.4 ± 26.3 Int J Cancer 2013;133: Validated FFQ % PreM, 43.5 y 45.9% PostM, 63.8 y

16 Extrapolating from one culture/ ethnic group to another?

17 Extrapolating from one culture/ ethnic group to another Confounding variables: Background diet Absorption and metabolism Others

18 Epidemiology Cohort Case-control Cross-sectional Is it useful for establishing efficacy? Ecological

19 Is It the Food/Food Component or Dietary Pattern? Traditional food Not considered a health food AJE 143 (11) suppl S36, abstract 141 Only 2.9% of the participants in the Iowa Women s Study ate tofu

20 Soybean Bioactives People eat soyfoods not isoflavones Isoflavones Protein/peptides Fatty acids ( LA) Protease inhibitors Phytate Phytosterols Saponins Phenolic acids

21 Epidemiology Cohort Case-control Is it useful? Cross-sectional Yes Ecological

22 Hierarchy of Evidence Systematic reviews and meta-analyses Correlation not causation (cells) Clinical trial Epidemiologic Animal In vitro (tissue) Prospective Case-control Cross-sectional Ecological Case reports Monkeys Pigs Rodents

23 Soybean Isoflavone Aglycones OH 7 A O C 1 2 Phytoestrogens R 1 5 R2 O 4 B OH Isoflavone R 1 R 2 % of total Genistein H OH 50 Daidzein H H 40 Glycitein OCH 3 H 10 Genistein Estradiol

24 Isoflavones OH 7 A O C 1 2 R 1 5 R2 O 4 B OH Preferentially bind to and transactivate ERβ in comparison with ER

25 ER vs. ERβ Different tissue distributions Different functions

26 THE LANCET Oncology 5: 174, 2004 In breast tissue ERβ transactivation inhibits the proliferative effect of ER transactivation

27 Isoflavones OH 7 A O C 1 2 R 1 5 R2 O 4 B OH Preferentially bind to and transactivate ERβ in comparison with ER Classified as selective estrogen receptor modulators (SERMs)

28 Molecular and cellular observations? In vivo effects

29 Comparison of the Clinical Effects of Soybean Isoflavones with Estrogen on Selected Endpoints Endpoint Isoflavones Estrogen Vaginal tissue 1 No Yes Bone mineral density No Yes Breast tissue 2 No Yes Hot flashes Yes Yes Endothelial function 3 Yes Yes Skin Yes? Yes 1 Vaginal maturation index 2 Density & cell proliferation 3 Flow mediated dilation

30 VMI Effects of Isoflavone-Rich Soy Protein 1 and Hormone Therapy 2 on Maturitas 2010;67:262 the Vaginal Maturation Index Isoflavone Placebo HT (n=20) (n=20) (n=20) 0 16 Weeks on treatment 1 24 g soy protein, 53 mg isoflavones 2 1 mg estradiol and 0.5 mg norethisterone acetate *

31 Score Effects of Isoflavone-Rich Soy Protein* and Hormone Therapy* on Somatic Symptoms in 60 Brazilian Women Soy, 24 g pro & 53 mg isoflav. HT, 1 mg E2 & 0.5mg norethisterone acetate Maturitas 67: 269, 2010 Placebo HT Soy 33% 55% 54% Week 0 Week 16

32 % of women with hot flashes The Hot Flash Hypothesis Isoflavones can mitigate the drop in estrogen levels Herman Adlercreutz, MD, PhD University of Helsinki, Finland Japan Canada USA China Exp Gerontol 29: 307, 1994; Maturitas 2006

33 Cumulative Number of Hot Flash Studies involving Soy or Isoflavones ( ) Mixed results Year of Publication

34 Metaanalysis 17 studies K Taku, National Institutes of Health (Japan), M Melby, University of Delaware; MS Kurzer, University of Minnesota; F Kronenberg, Stanford University; M Messina, Loma Linda University. Menopause 19: 776, 2012

35 Only trials intervening with extracts* derived from soybeans were eligible *1 trial used synthetic genistein

36 Percent in Hot Flash Frequency Isoflavones Placebo 13 trials N=1196 Upmalis, 2000 Scambia, 2002 Penotti, 2003 Nahas, 2007 Khaodhiar, 2008 Hachul, 2010 Gocan, 2007 Ferrari, 2009 Faure, 2002 Evans, 2011 D'Anna, 2007 Crisafulli, 2004 Campagnoli,

37 Percent in Hot Flash Frequency Isoflavones Placebo 13 trials N=1196 Net (p= ) Upmalis, 2000 Scambia, 2002 Penotti, 2003 Nahas, 2007 Khaodhiar, 2008 Hachul, 2010 Gocan, 2007 Ferrari, 2009 Faure, 2002 Evans, 2011 D'Anna, 2007 Crisafulli, 2004 Campagnoli,

38 Percent in Hot Flash Severity Isoflavones Placebo Nahas, 2007 Nahas, 2004 Khaodhiar, 2008 Jou, trials N=988 Net (p=0.001) Ferrari, 2009 Han, 2002 Gocan, 2007 Evans, 2011 D'Anna, 2007 Cheng,

39 Decrease in Hot Flash Frequency and Severity: Meta-analysis Results Symptom (Studies/N) Frequency (13/1196) Severity (9/988) Group Percent Decrease Placebo 29.6 Isoflavones 50.2 Net 20.6 Placebo 21.4 Isoflavones 47.6 Net 26.2

40 Isoflavone Profile of Two Commonly Used Soy Supplements Soybeans Supplements Whole soy Soygerm Genistein Daidzein Glycitein

41 2006; 13: extract products containing a minimum genistein dose are more effective at reducing hot flashes.

42 Ignored differences in the isoflavone profile of the intervention agents

43 Percent in Hot Flash Frequency Nahas, 2007 >18.8 mg genistein (median) Placebo 6 trials N=600 Net Hachul, 2010 Ferrari, 2009 Evans, 2011 D'Anna, 2007 Crisafulli, 2004 P = vs low genistein

44 Percent in Hot Flash Frequency Upmalis, 2000 Placebo 18.8 mg genistein Scambia, 2002 Penotti, trials N=596 Khaodhiar, 2008 Gocan, 2007 Faure, 2002 Net Campagnoli, 2005 P = vs high genistein

45 Isoflavones and the Alleviation of Menopausal Hot Flashes Expected 50-65% ( 50 mg total isoflavones) ( 19 mg genistein)

46 Number/day Effect of Isoflavones (90 mg/d) 1 on Hot Flash Frequency 2 in Chinese Postmenopausal Women months 6 months 16.3% % Placebo (n=33) Isoflavones (n=37) % genistein, 47.8% daidzein 2 0, none; 1, <3x/d; 2, 3-9x/d; 4, 10x/d 3 Women mostly abstained from eating soy 3 p<0.05. J Clin Biochem Nutr 53: 102, 2013

47 Menopause 19: 776, 2012 Baseline Hot Flash Frequency Number per day Unrelated to Efficacy Number of trials (n) Net % Decrease > * *P = 0.93, random effects model

48 Menopause 19: 776, 2012 Larger Effects in Studies more than 12 Weeks in Duration Weeks Number of trials (n) Net % Decrease > * *P = , random effects model

49 Endothelial Function ATVB 23: 168, 2003

50 Effects of Isoflavones on FMD 1 in PostM Women: Meta-analysis Results Studies (N) WMD 2 P value All studies Impaired endothelium (baseline FMD <5.2%) Healthy endothelium (baseline FMD 5.2%) Flow mediated dilation 2 Weighted mean difference. AJCN 91: 480, 2010

51 Carotid Intima-Media Thickness Measurement of the thickness of the artery wall Progression predicts coronary events

52 Soy and Arterial Wall Thickness: A Randomized Controlled Trial 350 postmenopausal women 3 year study Age: average, 60.9 years Diets Milk protein (25 grams per day) Soy protein (25 grams, 99 mg isofl.) Stroke 2011;42:

53 Thickness (mm) Carotid artery intima-media thickness progression rates Milk protein Soy protein 16% (P=0.35) Results analyzed by linear effects model. Stroke 42:3168, Years of study

54 Timing hypothesis

55 Carotid Artery Intima-Media Thickness Progression Rates 1 in the Soy Compared to the Milk Group Group % decrease All 16 Age (years) > m/year 2 p=0.05 (analyzed by linear mixed effects model adjusted for CIMT randomization strata Stroke 42: 3168,

56 Design Doesn t allow identification of biologically-active component(s) Nevertheless Consistency of findings with the Timing Hypothesis points toward isoflavones

57 US FDA-recognized Disease- Related Surrogate Endpoints Endpoint LDL-cholesterol Blood pressure Polyps Blood sugar Insulin resistance Bone density Impaired cognition Disease Coronary heart disease Colorectal cancer Diabetes Osteoporosis Dementia

58 Is soy isoflavone exposure safe for breast cancer patients?

59 Estrogen and Breast Cancer Conceptual basis for concern about isoflavones

60 Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: U.S. Preventive Services Task Force Recommendation Statement 2013 the use of estrogen alone results in a small reduction in the risk for developing or dying of invasive breast cancer. Ann Intern Med 2013;158:47-54

61 Clinical Trials Involving Soy Mammographic density (N=10*) Breast cell proliferation (N=5*) Nipple aspirate fluid (N=2*) Hormone levels (N=50*) No effects on markers of cancer risk Oncology 2013;430: *Number of studies

62 Effects of High-Dose Isoflavone Supplementation on Breast Tissue PTIG-2535 vs placebo (150 mg Gen, 74 mg Daid, 11 mg Gly) 6 months duration, N = 45 High-risk postmenopausal women Random fine-needle aspiration to assess cell proliferation

63 No Effect of Isoflavones (235 mg/d 1 ) on Breast Cell Proliferation 2 in 45 High-Risk Postmenopausal Women Difference between groups, p = Baseline Month Placebo Isoflavone No effects on cytology or Masood Score mg genistein 2 Ki-67 Labeling, % Cancer Prev Res 2012;5:

64 Combined Hormone Therapy Increases breast cell proliferation 4 to 10-fold Fertility Sterility 95: 1188, 2011; Breast Cancer Res Tx 78: 159, 2003

65 soy food intake should be encouraged in order to avoid mortality and recurrence Asian Pacific J Cancer Prev 14: 2407, 2013

66 Isoflavone Intake & Breast Cancer Prognosis: Pooled Analysis Shanghai Breast Cancer Survival Study Life After Cancer Epidemiology (USA) Women s Healthy Eating & Living (USA) N=9514 ½ postm ½ White AJCN 2012;96:123 Median follow up, 7.4 years 1171 Deaths 881 BCa-specific deaths 1348 Recurrences

67 Hazard Ratios for Post-diagnosis Isoflavone Intake and Breast Cancer Prognosis: Pooled Analysis Results Intake (mg/d) All cause mortality Breast cancer Mortality Recurrence < % CI: 1 (0.70, 1.10); 2 (0.64, 1.07); 3 (0.61, 0.92) *Mean, mg

68 Findings/Conclusions: Meaningful Western epidemiologic data largely unavailable Efficacy established primarily only for hot flashes Coronary (and skin) benefits very intriguing but still speculative Safety data reassuring

69 Findings/Conclusions: Insufficient justification for establishing a general NRV NRV possibly justified specifically for postmenopausal women If no NRV, intake recommendation from expert panel needed Reasonable intake: 50 to 80 mg/d