Phytoestrogens and Cardiovascular Disease
Where’s the Meat?
The potential role of phytoestrogens in postmenopausal women’s health has been an area of intense interest in recent years and, a report1 in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology adds to this body of knowledge. While there are several different classes of phytoestrogens, much of the recent phytoestrogen research has focused on the isoflavones, most common in soybeans, with some attention on lignans that are abundant in flaxseed. Since cardiovascular disease (CVD) is the leading cause of death in postmenopausal women, it is important that potential new therapies have proven benefits for CVD risk. Although there are many women taking phytoestrogens to maintain their health postmenopausally, there is only one rather small observational study that has linked phytoestrogen intake with cardiovascular morbidity or mortality.2 The results of this nested case-control study were that serum enterolactone concentrations (a lignan metabolite) were lower in men with acute coronary events compared with controls.2
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What is the evidence that phytoestrogens might reduce CVD risk? Data in animal models have shown that soy protein with its isoflavones, compared with isoflavone-devoid soy, can inhibit atherosclerosis.3–6⇓⇓⇓ One study in rabbits found that high doses of an isoflavone extract reduced atherosclerosis.7 Two studies in rabbits found an anti-atherogenic effect of flaxseed containing lignans,8,9⇓ and in one, treatment with the primary lignan in flax inhibited atherogenesis.9 Recent cardiovascular research with phytoestrogens in humans has focused largely on risk factors for CVD, including plasma lipoprotein concentrations and to a lesser extent vascular function, LDL oxidation, and blood pressure.10,11⇓ Much of the research in humans to date has been small, short-term clinical trials using relatively high amounts of soy, isoflavone, or flaxseed supplementation. Taken on balance, these studies suggest that soy with higher amounts of isoflavones is better for plasma lipoprotein concentrations (lower LDL cholesterol and sometimes higher HDL cholesterol),12,13⇓ inhibition of LDL oxidation potential,14 and blood pressure.12,15⇓ The data regarding vascular function are mixed with little evidence that soy with isoflavones can improve endothelial-dependent vascular reactivity in postmenopausal women (and that it might have an adverse effect in men),15 but that isoflavone pills improve arterial elasticity in postmenopausal women.16,17⇓ There is scant evidence that isoflavone pills have benefits for other CVD risk factors.10 There are fewer studies regarding cardiovascular effects of lignans in humans, but the few clinical trials tend to find improvements in plasma lipid concentrations with flaxseed supplementation.18 The phytoestrogen amounts used in these clinical trials, when eaten in foods at naturally occurring levels, are generally higher than can be incorporated easily into a western-type diet. Therefore, the potential impact on postmenopausal health is constrained.
Van der Schouw and colleagues1 found that higher “usual” intake of phytoestrogens in a Dutch population was associated with lower aortic stiffness. This study was done within one of the two Dutch cohorts included in the European Investigation into Cancer and nutrition (EPIC) and drew on a large population for whom diet had been measured 2 to 7 years before the current study (n=17 365 women enrolled in this EPIC cohort). Phytoestrogen intake in the course of a year was estimated from a semiquantitative food frequency questionnaire and expressed as intake per day. Aortic stiffness in this study was measured by pulse wave velocity. Although observational studies cannot conclude causality between exposure and outcome, the information that can be gleaned is invaluable, including evidence about different levels of intake, longer-term exposure than is usual in clinical trials, and outcomes that might require a longer time to be affected.
This study1 has added several new dimensions to the information regarding phytoestrogen effects on CVD in postmenopausal women. First, daily phytoestrogen intake (isoflavones and lignans) was very low, ≈100 times lower than has been generally used in clinical trials of soy phytoestrogens. This low intake might make one skeptical of any causal association, but it might also suggest that low phytoestrogen intake for a long period of time can have beneficial effects and/or that daily phytoestrogen intake is not necessary to derive benefits. Although food frequency questionnaires are generally a rather imprecise method to “measure” diet, the impact of this sort of random error is generally to result in a null finding, ie, no association between the dietary factor and outcome. Interestingly, two other recent studies have reported associations between usual phytoestrogen intake and cardiovascular disease risk factors in postmenopausal women eating low amounts of phytoestrogens in the United States.19,20⇓ One study in southern California19 reported that higher isoflavone intake, estimated in the previous year, was associated with lower measures of obesity, fasting insulin concentrations, and post-challenge insulin and higher HDL cholesterol concentrations. The other study,20 done within the Framingham Offspring Study cohort, found that higher lignan intake was associated with lower waist-hip ratio, lower plasma triglycerides, and a lower cardiovascular risk metabolic score; higher isoflavone intake was related to lower plasma triglycerides and an improved cardiovascular risk metabolic score. The cardiovascular risk metabolic score incorporated systolic blood pressure or antihypertensive medication use, diastolic blood pressure, plasma triglycerides or use of cholesterol-lowering medications, plasma HDL cholesterol, waist-hip ratio, and body mass index, and a higher score indicated a more adverse CVD risk profile. These studies adjusted for a variety of demographic and lifestyle factors that are indicative of a healthy lifestyle. Therefore, one cannot dismiss the possibility that these lower phytoestrogen amounts might be biologically active.
A second new component of this study1 is the outcome aortic stiffness, which might be considered an integrated indicator of cardiovascular health. While this outcome has been measured for many years, it is only relatively recently that large epidemiologic studies have reported associations between aortic stiffness and age, sex, heart rate, blood pressure, carbohydrate metabolism measures, adiposity, physical activity, smoking, and plasma lipid concentrations.21–23⇓⇓ In addition, aortic stiffness is associated with indicators of atherosclerosis such as carotid artery intima media thickness22,24⇓ and future coronary events25 and is reported to be an independent predictor of cardiovascular mortality.26,27⇓ Aortic stiffness, whether an indicator of higher atherosclerotic burden, worsened arterial function, arterial degeneration, or some other vascular process seems to be a useful measure of cardiovascular health and predictive of cardiovascular morbidity and mortality. Because it seems a reproducible measure that can be done with modest equipment and in large population studies, it is surprising more studies have not used this outcome. In the absence of information about phytoestrogen effects on cardiovascular morbidity or mortality, this reported association between phytoestrogen intake and aortic stiffness is an important advance in knowledge.
In observational studies, there are always competing hypotheses that must be considered. Phytoestrogen intake, particularly in a western population, might just be a surrogate maker for a healthy lifestyle. Thus, other lifestyle and demographic factors must be considered for their potential confounding influence. Van der Schouw et al1 considered age, body mass index, smoking, physical activity, mean arterial pressure, time since menopause, energy intake, fiber intake, fruit intake, vegetable intake, alcohol intake, blood glucose, and HDL cholesterol as potential confounders, thus, providing more plausibility to the independent association between low phytoestrogen intake and aortic stiffness. It is possible that phytoestrogen intake is a marker for replacement of some less healthful food(s), but because substitution of plant foods for other foods is the recommendation of nutrition educators, including the American Heart Association,28 this study1 supports that recommendation. The finding that a linear dose-response association between isoflavone or lignan intake and aortic stiffness was only apparent in women that were postmenopausal for longer adds additional biologic plausibility to an estrogen-like effect of the phytoestrogens. That the phytoestrogens have biologic effects on some indicators of vascular function is supported by two clinical trials that found beneficial effects of isoflavone pills on systemic arterial compliance, an indicator of arterial elasticity.16,17⇓
So what can we conclude from this report, and what questions remain? The association between aortic stiffness and lignan or isoflavone intake seems plausible. The authors adjusted for lifestyle and demographic measures, providing some evidence of an association that is independent of other healthy lifestyle components. While the analyses consider the associations with phytoestrogen intake, the isoflavones and lignans are components of plant foods, and therefore, the conclusions relate to consumption of lignan- and isoflavone-rich foods, not isolated phytoestrogens. This is important, because it seems likely, at least for isoflavones, that they are less effective when removed from their food matrix.29 Therefore, phytoestrogen-rich foods should be recommended. The evidence that even small amounts of phytoestrogen-containing foods might provide cardiovascular benefit enhances the potential applicability, because more people might be able to achieve and sustain this lower intake. To document the effects of lower phytoestrogen intake, clinical trials and studies in animal models should evaluate lower amounts of isoflavone- and lignan-containing foods given for longer times and use endpoints that measure cumulative effects, such as aortic stiffness and atherosclerosis. In addition, dose-response trials should be done to determine optimal doses for the cardiovascular system, bone, and cognitive function, while being safe for breast and endometrium. Finally, prospective studies evaluating the effects of phytoestrogens on cardiovascular morbidity and mortality should be done. Observational cohort studies can provide evidence about these associations between phytoestrogen intake and CVD events and may help direct future clinical trials. If phytoestrogens are to be considered an alternative to traditional hormone replacement therapy, then clinical trials with CVD event outcomes must be undertaken. The study by van der Schouw et al1 adds important information to our understanding of phytoestrogen-rich foods and cardiovascular health. However, there remain many questions important for the health of postmenopausal women, and many women are not waiting for the evidence.
- ↵Van der Schouw YT, Pijpe A, Lebrun CEI, Bots ML, Peeters PHM, van Staveren WA, Lamberts SWJ, Grobbee DE. Higher usual dietary intake of phytoestrogens is associated with lower aortic stiffness in postmenopausal women. Arterioscler Thromb Vasc Biol. 2002; 22: 1316–1322.
- ↵Anthony MS, Clarkson TB, Bullock BC, Wagner JD. Soy protein versus soy phytoestrogens in the prevention of diet-induced coronary artery atherosclerosis of male cynomolgus monkeys. Arterioscler Thromb Vasc Biol. 1997; 17: 2524–2531.
- ↵Adams MR, Golden DL, Anthony MS, Register TC, Williams JK. The inhibitory effect of soy protein isolate on atherosclerosis in mice does not require the presence of LDL receptors or alteration of plasma lipoproteins. J Nutr. 2002; 132: 43–49.
- ↵Kirk EA, Sutherland P, Wang SA, Chait A, LeBoeuf RC. Dietary isoflavones reduce plasma cholesterol and atherosclerosis in C57BL/6 mice but not LDL receptor-deficient mice. J Nutr. 1998; 128: 954–959.
- ↵Yamakoshi J, Piskula MK, Izumi T, Tobe K, Saito M, Kataoka S, Obata A, Kikuchi M. Isoflavone aglycone-rich extract without soy protein attenuates atherosclerosis development in cholesterol-fed rabbits. J Nutr. 2000; 130: 1887–1893.
- ↵Prasad K. Reduction of serum cholesterol and hypercholesterolemic atherosclerosis in rabbits by secoisolariciresinol diglycoside isolated from flaxseed. Circulation. 1999; 99: 1355–1362.
- ↵Anthony MS. Soy/isoflavones and risk factors for cardiovascular disease.In: Gilani S, Anderson J, eds. Phytoestrogens and Health. Champagne, Ill: AOCS Press. 2002: 268–289.
- ↵Thompson LU, Ward WE. Flaxseed lignans: health benefits, bioavailability, and safety.In: Gilani S, Anderson J, eds. Phytoestrogens and Health. Champagne, Ill: AOCS Press. 2002: 405–426.
- ↵Wangen KE, Duncan AM, Xu X, Kurzer MS. Soy isoflavones improve plasma lipids in normocholesterolemic and mildly hypercholesterolemic postmenopausal women. Am J Clin Nutr. 2001; 73: 225–231.
- ↵Wiseman H, O’Reilly JD, Adlercreutz H, Mallet AI, Bowey EA, Rowland IR, Sanders TAB. Isoflavone phytoestrogens consumed in soy decrease F2-isoprostane concentrations and increase resistance of low-density lipoprotein to oxidation in humans. Am J Clin Nutr. 2000; 72: 395–400.
- ↵Nestel PJ, Yamashita T, Sasahara T, Pomeroy S, Dart A, Komesaroff P, Owen A, Abbey M. Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women. Arterioscler Thromb Vasc Biol. 1997; 17: 3392–3398.
- ↵Jenkins DJA, Kendall CWC, Vidgen E, Agarwal S, Rao AV, Rosenberg RS, Diamandis EP, Novokmet R, Mehling CC, Perera T, Griffin LC, Cunnane SC. Health aspects of partially defatted flaxseed, including effects on serum lipids, oxidative measures, and ex-vivo androgen and progestin activity: a controlled crossover trial. Am J Clin Nutr. 1999; 69: 395–402.
- ↵Goodman-Gruen D, Kritz-Silverstein D. Usual dietary isoflavone intake is associated with cardiovascular disease risk factors in postmenopausal women. J Nutr. 2001; 131: 1202–1206.
- ↵De Kleijn MJJ, van der Schouw YT, Wilson PWF, Grobbee DE, Jacques PF. Dietary intake of phytoestrogens is associated with a favorable metabolic cardiovascular risk profile in postmenopausal US women: The Framingham Study. J Nutr. 2002; 132: 276–282.
- ↵Van Popele NM, Grobbee DE, Bots ML, Asmar R, Topouchian J, Reneman RS, Hocks APG, van der Kuip DAM, Hofman A, Witteman JCM. Association between arterial stiffness and atherosclerosis: The Rotterdam Study. Stroke. 2001; 32: 454–460.
- ↵Boutouyrie P, Tropeano AI, Asmar R, Gautier I, Benetos A, Lacolley P, Laurent S. Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study. Hypertension. 2002; 39: 10–15.
- ↵Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere P, Benetos A. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension. 2001; 37: 1236–1241.
- ↵Meaume S, Benetos A, Henry OF, Rudnichi A, Safar ME. Aortic pulse wave velocity predicts cardiovascular mortality in subjects >70 years of age. Arterioscler Thromb Vasc Biol. 2001; 21: 2046–2050.
- ↵Krauss RM, Eckel RH, Howard B, Appel LJ, Daniels SR, Deckelbaum RJ, Erdman JW, Kris-Etherton P, Goldberg IJ, Kotchen TA, Lichtenstein AH, Mitch WE, Mullis R, Robinson K, Wylie-Rosett J, St. Jeor S, Suttie J, Tribble DL, Bazzarre TL. AHA dietary guidelines revision 2000: a statement for healthcare professionals from the nutrition committee of the American Heart Association. Circulation. 2000; 102: 2284–2299.
- ↵Anthony MS, Blair RM, Clarkson TB. Neither isoflavones nor the alcohol-extracted fraction added to alcohol-washed soy protein isolate restores the lipoprotein effects of soy protein isolate. J Nutr. 2002; 132: 583S.Abstract.