WISH was designed to study the cardiovascular and cognitive (thinking, memory) effects of high-dose soy-isoflavone supplementation in women. In this double-blinded, placebo-controlled trial, 350 postmenopausal women 45 to 92 years of age without diabetes and cardiovascular disease were randomized to 2 evenly divided daily doses of 25 g soy protein containing 91 mg aglycon isoflavone equivalents or to placebo for up to 3.5 years.
This study was supported by National Institutes of Health from the National Center for Complementary and Alternative Medicine, the Office of Dietary Supplements, and the Office of Research on Women’s Health. Solae LLC (St Louis, MO) provided the study products gratis.
Registered at clinicaltrials.gov under NCT00118846
Isoflavone soy protein supplementation and atherosclerosis progression in healthy postmenopausal women: a randomized controlled trial.
Hodis HN, Mack WJ, Kono N, Azen SP, Shoupe D, Hwang-Levine J, Petitti D, Whitfield-Maxwell L, Yan M, Franke AA, Selzer RH; Women’s Isoflavone Soy Health Research Group.
Stroke. 2011 Nov;42(11):3168-75.
BACKGROUND AND PURPOSE:
Although epidemiological and experimental studies suggest that dietary intake of soy may be cardioprotective, use of isoflavone soy protein (ISP) supplementation as a primary preventive therapy remains unexplored. We determined whether ISP reduces subclinical atherosclerosis assessed as carotid artery intima-media thickness progression.
In a double-blind, placebo-controlled trial, 350 postmenopausal women 45 to 92 years of age without diabetes and cardiovascular disease were randomized to 2 evenly divided daily doses of 25 g soy protein containing 91 mg aglycon isoflavone equivalents or placebo for 2.7 years.
Overall, mean (95% CI) carotid artery intima-media thickness progression rate was 4.77 (3.39-6.16) μm/year in the ISP group and 5.68 (4.30-7.06) μm/year in the placebo group. Although carotid artery intima-media thickness progression was reduced on average by 16% in the ISP group relative to the placebo group, this treatment effect was not statistically significant (P=0.36). Among the subgroup of women who were randomized within 5 years of menopause, ISP participants had on average a 68% lower carotid artery intima-media thickness progression rate than placebo participants 2.16 (-1.10 to 5.43) versus 6.79 (3.56-10.01) μm/year (P=0.05). ISP supplementation had a null effect on women who were more than 5 years beyond menopause when randomized. There were no major adverse events from ISP supplementation.
ISP supplementation did not significantly reduce subclinical atherosclerosis progression in postmenopausal women. Subgroup analysis suggests that ISP supplementation may reduce subclinical atherosclerosis in healthy young (median age, 53 years) women at low-risk for cardiovascular disease who were less than 5 years postmenopausal. These first trial results of their kind warrant further investigation.
Long-term soy isoflavone supplementation and cognition in women: a randomized, controlled trial.
Henderson VW, St John JA, Hodis HN, Kono N, McCleary CA, Franke AA, Mack WJ; WISH Research Group.
To determine the cognitive effects of long-term dietary soy isoflavones in a daily dose comparable to that of traditional Asian diets.
In the double-blind Women’s Isoflavone Soy Health trial, healthy postmenopausal women were randomly allocated to receive daily 25 g of isoflavone-rich soy protein (91 mg of aglycone weight of isoflavones: 52 mg of genistein, 36 mg of daidzein, and 3 mg glycitein) or milk protein-matched placebo. The primary cognitive endpoint compared between groups at 2.5 years was change from baseline on global cognition, a composite of the weighted sum of 14 neuropsychological test score changes. Secondary outcomes compared changes in cognitive factors and individual tests.
A total of 350 healthy postmenopausal women aged 45-92 years enrolled in this trial; 313 women with baseline and endpoint cognitive test data were included in intention-to-treat analyses. Adherence in both groups was nearly 90%. There was no significant between-group difference on change from baseline in global cognition (mean standardized improvement of 0.42 in the isoflavone group and 0.31 in the placebo group; mean standardized difference 0.11, 95% confidence interval [CI] -0.13 to 0.35). Secondary analyses indicated greater improvement on a visual memory factor in the isoflavone group (mean standardized difference 0.33, 95% CI 0.06-0.60) but no significant between-group differences on 3 other cognitive factors or individual test scores, and no significant difference within a subgroup of younger postmenopausal women.
For healthy postmenopausal women, long-term dietary soy isoflavone supplementation in a dose comparable to that of traditional Asian diets has no effect on global cognition but may improve visual memory. Classification of evidence: This study provides Class I evidence that long-term dietary supplementation with isoflavone-rich soy protein does not improve global cognition of healthy postmenopausal women.
Equol production changes over time in postmenopausal women.
Franke AA, Lai JF, Halm BM, Pagano I, Kono N, Mack WJ, Hodis HN.
Equol (EQ) is produced by intestinal bacteria from the soy isoflavone daidzein (DE) in 30%-60% of the population and is believed to provide benefits from soy intake. A robust EQ status definition is lacking, and it is uncertain whether EQ is formed consistently within an individual and ceases upon oral antibiotic treatment. In a randomized, double-blind, placebo-controlled soy intervention trial with 350 postmenopausal women, DE and EQ were analyzed by liquid chromatography/tandem mass spectrometry at baseline and every 6 months over 2.5 years in overnight urine, spot urine and plasma. Equol production changes and status (remaining an EQ producer or nonproducer or changing towards an EQ producer or nonproducer) were assessed. Equol status was determined most dependably by overnight urine applying as cutoff a ratio of EQ/DE≥0.018 with a DE threshold higher or equal 2 nmol/mg creatinine: the soy and placebo groups had approximately 30% consistent EQ producers during the study, but 14% and 35%, respectively, changed EQ status (mean 1.4-1.7 times), while 27% and 17%, respectively, had antibiotic treatment (P<.01 for inverse association). No significant trend in change of EQ production or status was observed when overnight urine was limited to collections closest to before and after antibiotic treatment. Similarly, antibiotic type or class, duration, dose or time between antibiotic treatment and overnight urine collection showed no consistent influence on EQ production. Equol production can markedly change intraindividually over 2.5 years, and antibiotic treatment impacts it inconsistently. Factors other than antibiotic treatment must be considered as causes for EQ production changes.
Urine accurately reflects circulating isoflavonoids and ascertains compliance during soy intervention.
Franke AA, Hebshi SM, Pagano I, Kono N, Mack WJ, Hodis HN.
Isoflavonoids (IFL) may protect against chronic diseases, including cancer. IFL exposure is traditionally measured from plasma (PL), but the reliability of urine is uncertain. We assessed whether IFL excretion in overnight urine (OU) or spot urine (SU) reliably reflects IFLs in PL and the usefulness of the three matrices to determine soy intake compliance.
In a randomized, double-blind, placebo-controlled soy intervention trial with 350 postmenopausal women, IFLs (daidzein, genistein, glycitein, equol, O-desmethylangolensin, dihydrodaidzein, dihydrogenistein) were analyzed by liquid chromatography/mass spectrometry in OU, SU, and PL collected at baseline and every 6 months over 2.5 years.
High between-subject intraclass correlations between all three matrices (median, 0.94) and high between-subject Pearson correlations (median r(OU-PL) = 0.80; median r(SU-PL) = 0.80; median r(OU-SU) = 0.92) allowed the development of equations to predict IFL values from any of the three matrices. Equations developed from a randomly selected 87% of all available data were valid because high correlations were found on the residual 13% of data between equation-generated and measured IFL values (median r(OU-PL) = 0.86; median r(SU-PL) = 0.78; median r(OU-SU) = 0.84); median absolute IFL differences for OU-PL, SU-PL, and OU-SU were 8.8 nmol/L, 10.3 nmol/L, and 0.28 nmol/mg, respectively. All three matrices showed highly significant IFL differences between the placebo and soy intervention group at study end and highly significant correlations between IFL values and counted soy doses in the intervention group.
OU and SU IFL excretion reflect circulating PL IFL levels in healthy postmenopausal women accurately.
Noninvasively-collected urine can be used to reliably determine systemic IFL exposure and soy intake compliance.
Associations between urine excretion of isoflavonoids and cognition in postmenopausal women in the Women’s Isoflavone Soy Health clinical trial.
St John JA, Henderson VW, Hodis HN, Kono N, McCleary CA, Franke AA, Mack WJ.
J Am Geriatr Soc. 2014 Apr;62(4):629-35.
To determine effect of change in urine excretion of isoflavonoids on cognitive change.
Post hoc analysis of isoflavonoid exposure (mean 2.7 years) during the randomized, placebo-controlled, double-blind Women’s Isoflavone Soy Health trial.
Healthy postmenopausal women (N = 350).
Twenty-five grams of isoflavone-rich soy protein (91 mg of aglycone weight isoflavones: 52 mg genistein, 36 mg daidzein, 3 mg glycitein) or milk protein-matched placebo provided daily.
Overnight urine excretion, fasting plasma levels of isoflavonoids, and cognitive function measured at baseline and endpoint.
Three hundred women (age: mean 61, range 45-92) completed both cognitive assessments and did not use hormone replacement therapy during the trial. Mean on-trial change from baseline in urine excretion of isoflavonoids was not significantly associated with change in a composite score of global cognition (P = .39). Secondary analyses indicated that change in urine excretion of isoflavonoids was inversely associated with change in a factor score representing general intelligence (P = .02) but not with factor scores representing verbal or visual episodic memory. Mean differences in this general intelligence factor score between women in the lowest and highest quartiles of isoflavonoid change were equivalent to an approximate 4.4-year age-associated decline. Analyses based on plasma isoflavonoid levels yielded similar but attenuated results.
In healthy postmenopausal women, long-term changes in isoflavonoids are not associated with global cognition, supporting clinical trial results, although greater isoflavonoid exposure from dietary supplements is associated with decrements in general intelligence but not memory; this finding requires confirmation in future studies.
Effect of isoflavone soy protein supplementation on endometrial thickness, hyperplasia, and endometrial cancer risk in postmenopausal women: a randomized controlled trial.
Quaas AM, Kono N, Mack WJ, Hodis HN, Felix JC, Paulson RJ, Shoupe D.
Menopause. 2013 Aug;20(8):840-4.
This study aims to determine whether long-term isoflavone soy protein (ISP) supplementation affects endometrial thickness and rates of endometrial hyperplasia and cancer in postmenopausal women.
In this randomized, double-blind, placebo-controlled trial, 350 postmenopausal women aged 45 to 92 years were randomized to a total daily dose of 154 mg of ISP or a milk protein-matched placebo for a 3-year period. Women with a surgically absent uterus were excluded from the analysis (final study population, N = 224). The main outcome measures were as follows: mean change in endometrial thickness on transvaginal ultrasound from baseline until up to 36 months of follow-up and the incidence of endometrial sampling, endometrial hyperplasia, and endometrial cancer.
A total of 666 visits among 224 participants were evaluated. Treatment groups did not significantly differ on the mean baseline or on-trial changes in endometrial thickness. Of the 103 placebo-treated participants, 7 (6.8%) underwent endometrial biopsy; 6 (85.7%) of these biopsies were benign. One woman in the placebo group was diagnosed with complex endometrial hyperplasia with atypia and underwent hysterectomy. The pathology result from this surgical operation was stage IB endometrial cancer. Of the 121 participants in the soy group, 9 (7.4%) underwent endometrial biopsy. The results were benign in all nine cases (100%). Although the rate of hyperplasia/malignancy was higher in the placebo group (14.3% vs 0%), the difference was not statistically significant.
Three-year ISP supplementation has no effect on endometrial thickness or on the rates of endometrial hyperplasia and cancer in postmenopausal women.