In the overall cohort of healthy postmenopausal women, ISP supplementation did not significantly reduce the progression of subclinical atherosclerosis relative to placebo. In subgroup analysis, ISP supplementation significantly reduced progression of subclinical atherosclerosis in women who were within 5 years of menopause with a null effect on the progression of subclinical atherosclerosis in the women who were >5 years beyond menopause when randomized.
The age range for this trial was developed to address the effect of ISP supplementation over the postmenopausal age range for potential generalization to all postmenopausal women. Although the trial was not specifically designed to test the effects of ISP supplementation in younger women, the trial results indicate that a beneficial treatment effect may be limited to women who initiate ISP supplementation when close to menopause (within <5 years). This suggests a potential benefit over a narrower age range. The approximate 46% reduction in progression of CIMT in the ISP versus placebo group in the women <55 years of age is consistent with this possibility. It is possible that the broad age range of our population may have diluted a possible treatment effect of ISP supplementation in younger postmenopausal women.
Findings from WISH are consistent with data that support the timing hypothesis that posits that CVD is reduced in young postmenopausal women who initiate hormone therapy in close proximity to menopause versus a null CVD effect in women who initiate therapy when distant from menopause (24
). Accumulating data from human and animal studies indicate that postmenopausal hormone therapy has little effect in reversing atherosclerosis once it is established, whereas it significantly reduces the extent of atherosclerosis if initiated at an early stage (24
). Animal studies have demonstrated the same phenomenon whereby soy isoflavone administration does not reverse established atherosclerosis (34
) but prevents atherosclerosis development (35
). Recently, the timing hypothesis has been shown to be operative with the SERM raloxifene whereby women <60 years of age who received SERM therapy had a statistically significant reduction in CVD whereas women older than 60 years of age had no CVD benefit relative to placebo (37
). Our subgroup analysis suggests that ISP may be the third class of estrogen receptor-binding molecules (4
) to behave in accordance with the timing hypothesis (33
Equol, a product of intestinal bacterial metabolism of daidzein is superior to all other isoflavones in its antioxidant activity (38
). However, equol is not produced by all individuals and it has been suggested that the maximal clinical responses to ISP are observed in equol-producers versus equol non-producers (38
). Since the clinical effectiveness of ISP may be a function of the ability to biotransform daidzein to the more potent estrogenic isoflavone equol, we examined the effect of ISP on atherosclerosis progression in equol producers versus equol non-producers. We found no difference in atherosclerosis progression comparing placebo to treatment groups defined by equol production.
Although shown to require the estrogen receptor (ER) to be anti-atherogenic (40
), soy isoflavones may also have non-ER-mediated anti-atherogenic effects through traditional CVD risk factors including alteration of lipids and blood pressure (12
). The ISP effects on these 2 major CVD risk factors are inconsistent across the literature (45
). We found no effect of ISP on blood pressure but did detect a 2-fold greater increase in HDL-C in the ISP-treated group relative to the placebo-treated group. We previously reported that 17β-estradiol therapy significantly reduced CIMT progression with approximately 30% of the variability of this effect due to lipid alteration including the HDL-C raising effect of estrogen therapy (24
Epidemiological, cross-cultural and migrant studies indicate that the Western diet plays an important role in the incidence of coronary heart disease as well as breast, ovary, colon and prostate cancer (7
). Among Pacific Rim (Asian) countries where the intake of ISP is very high, the incidence of these chronic diseases is much lower than in Western countries (6
). In the context of non-human primate studies in which dietary intake was completely replaced with ISP and epidemiological studies of Asian populations, the effects of ISP may not have been fully expressed in WISH where ISP was used as a supplement to rather than a replacement of a Western diet. Longer or sole exposure to ISP as in Asian populations may be required for the full expression of the effects of ISP on atherosclerosis progression. Although we did not find a difference in treatment effect across ethnic groups, the treatment group difference in CIMT progression was of borderline significance in the small subgroup of Asian women. Additionally, within the ISP-treatment group, the rate of CIMT progression in Asians was less than half the CIMT rate as the other ethnic groups. Taken together, the cumulated data suggest that a potential gene-ISP interaction may exist for the expression of a beneficial effect of ISP.
WISH was the largest and longest randomized controlled trial of ISP supplementation examining CVD in general and progression of atherosclerosis specifically; isoflavone dosage was high, tolerable and without serious adverse events. As such, participant withdrawal was low and compliance with study products was excellent (about 90%) with confirmed high plasma concentrations (31
). However, sample size and duration of therapy may not have been sufficient to detect a smaller change in atherosclerosis progression than that originally hypothesized and used to guide our sample size estimates. As the first large-scale randomized controlled trial examining the effects of ISP on atherosclerosis progression, certain limitations result from the disadvantage of not having antecedent trials upon which to guide design. Practicality mandated use of only 1 readily available form of high-dose ISP such that the results may not be necessarily generalizable to isolated individual isoflavones, other classes of phytoestrogens more abundant in non-soy food products (e.g., flavones, coumestans and lignans) or to the more recently developed equol products. Duration of therapy may be a limitation since the cardioprotective effect of ISP observed in epidemiological studies is in populations of individuals who are exposed over a life-time to high levels of soy beginning in-utero and to a large dietary ingestion of soy from birth. Another limitation of the trial results from the disadvantage of experience in administration of ISP in different populations of women since our results suggest that certain populations of women such as Asians and women in close proximity to menopause (younger women in a narrower age range) may have a more effective response to ISP supplementation. While these latter findings are consistent with those predicted from epidemiological studies our findings are limited by the number of subgroup analyses performed.