The effect of supplementation with isoflavones on plasma lipids and oxidisability of low density lipoprotein in premenopausal women

Results of recent clinical studies have lead to the hypothesis that isoflavones are cardioprotective. The aims of this trial were to determine the effect of supplementation with isoflavonoid phytoestrogens on plasma cholesterol concentrations and its distribution among lipoproteins and whether supplementation with isoflavones influences oxidisability of low density lipoprotein (LDL) ex vivo. Fourteen healthy premenopausal women participated in a randomised cross-over trial lasting four menstrual cycles (approximately 4 months). The subjects were asked to consume 86 mg of isoflavones daily for the duration of two menstrual cycles followed by placebo for an equivalent period, or vice versa. Venous blood samples were collected initially and at the end of the second and fourth menstrual cycles for the determination of plasma lipid concentrations and the resistance of LDL to copper-induced oxidation ex vivo. Accustomed dietary intake of isoflavones and lignans during the placebo period were 6.87+/-3.0 and 1.80+/-0.22 mg/day (mean+/-S.E.M.), respectively, and these did not change during the supplementation period. The intake of other dietary components remained constant during the trial. Supplementation resulted in a 5-fold increase in urinary isoflavone excretion (12.2+/-14.2 versus 70.1+/-10.3 micromol/24 h, placebo and isoflavone periods, respectively, P=0.0001). No changes in the oxidisability of LDL (lag time of 32.9+/-3.1 versus 30.4+/-2.9 min) or the plasma concentrations of total cholesterol (4.03+/-0.21 versus 4.11+/-0.18 mmol/l) or triacylglycerol (0.67+/-0.04 versus 0.73+/-0.06 mmol/l) were observed following supplementation. However a significant period effect (P=0.024) was observed and a trend towards a carryover effect (P=0.086) was noted for the concentration of HDL(3) cholesterol. Further studies are required to clarify the potential effect of isoflavones on HDL metabolism and the interaction with plasma steroid hormones during the menstrual cycle.     

Systematic review of soy isoflavone supplements on osteoporosis in women

ObjectiveTo clarify the effect of soy isoflavones on prevention of osteoporosis, and the effective dosage of soy isoflavones and its duration.MethodsRandom control trials that investigated the association of soy isoflavones and osteoporosis were included in the meta-analysis by researching MEDLINE, EMBASE and the Chinese Biomedical Database up to October 2011. The Rev Man software was used for all of the statistical analysis.ResultsThe present meta-analysis found that soy isoflavones significantly increased the bone mineral density by 54% and decreased the bone resorption marker urinary deoxypyridinoline (DPD) by 23% compared to baseline in women. Using random effects model, the effect of isoflavones on bone mineral density (BMD) regarding menopausal status and isoflavone dose revealed higher weighted mean difference changes were found in postmenopausal women and isoflavone dose above 75 mg/d. Subgroup analysis of trials with menopausal status, supplement type, isoflavone dose and intervention duration that used soy isoflavone extracts resulted in significant different overall effect of DPD using by random effects model. Sensitivity analysis indicated that the effect of soy isoflavones on BMD and DPD was robust.ConclusionsThe present meta-analysis reveals that soy isoflavone supplements significantly increase bone mineral density and decrease the bone resorption marker urinary DPD. It shows no significant effect on bone formation markers serum bone alkaline phosphatase. The significant effect of soy isoflavones on BMD and urinary DPD is relative to menopausal status, supplement type, isoflavone dose and intervention duration.     

Soy isoflavones do not affect bone resorption in postmenopausal women: a dose-response study using a novel approach with 41Ca

INTRODUCTION: The purpose of this 3-way crossover study was to identify the effective dose of soy protein isolate enriched with isoflavones for suppressing bone resorption in postmenopausal women using a novel, rapid assessment of antibone resorbing treatments. METHODS: Thirteen postmenopausal women (>or=6 yr since menopause) were predosed with 41Ca iv. After a 200-d baseline period, subjects were given 43 g soy protein/d that contained 0, 97.5, or 135.5 mg total isoflavones in randomized order. The soy protein isolate powder was incorporated into baked products and beverages. Each 50-d intervention phase was preceded by a 50-d pretreatment phase for comparison. Serum isoflavone levels and biochemical markers were measured at the end of each phase. Twenty-four-hour urine samples were collected approximately every 10 d during each phase for 41Ca/Ca analysis by accelerator mass spectrometry. RESULTS: Serum isoflavone levels reflected the amount of isoflavones consumed in a dose-dependent manner. None of the isoflavone levels had a significant effect on biochemical markers of bone turnover, urinary cross-linked N teleopeptides of type I collagen and serum osteocalcin, or bone turnover as assessed by urinary 41Ca/Ca ratios. CONCLUSIONS: Soy protein with isoflavone doses of up to 135.5 mg/d did not suppress bone resorption in postmenopausal women. This is the first efficacy trial using the novel technique of urinary 41Ca excretion from prelabeled bone.     

Evidence of estrogenic effect by the three-month-intervention of isoflavone on vaginal maturation and bone metabolism in early postmenopausal women

Objective of the present study is to determine the estrogenic effect of isoflavone on vaginal epithelia and bone metabolism in early postmenopausal women. Twenty-two postmenopausal women were randomly assigned to either a group that was given isoflavone extract (61.8 mg) for three months or a control group that was given placebo. We measured the L2-4 bone mineral density (BMD) before and 3 months after treatment by dual X-ray absorptiometry (DXA). Blood and urine samples were obtained from the women before and 3 months after treatment. We measured FSH using radioimmunoassay and, urinary pyridinoline and deoxypyridinoline levels by HPLC. For endocrine cytology, vaginal smears were collected before and 3 months after the treatment. Three months after the treatment, the serum FSH levels and the BMD values did not significantly differ between the two groups. Urinary excretion of isoflavone was significantly higher in the group given isoflavone compared with that given placebo (p<0.03). Numbers of parabasal and intermediate types of cells were significantly decreased (58.2 +/- 12.4% to 25.0 +/- 10.7%; p<0.05) and increased (24.1 +/- 8.7% to 63.7 +/- 10.7%; p<0.05), respectively in the isoflavone group, but remained unchanged in the control group. Urinary pyridinoline excretion was significantly decreased (49.6% vs. before, p<0.01 by paired t-test) in the isoflavone group. The intake of 60 mg of isoflavone daily for 3 months produced maturational changes of vaginal epithelia without affecting serum FSH levels, and could possibly slow down bone turnover rates as judged by decreased urinary pyridinoline excretion.     

Effects of soy isoflavones on markers of bone turnover in premenopausal and postmenopausal women

Soy isoflavones are hypothesized to exert hormonal effects in women and thus may play a role in bone metabolism throughout life. In 2 randomized, cross-over studies, 14 pre- and 17 postmenopausal women were given 3 soy protein isolates containing different amounts of isoflavones [control, 0.13; low isoflavone (low-iso), 1.00; and high-iso, 2.01 mg/kg body wt/day, averaging 8, 65, and 130 mg/day, respectively], for over 3 months each. Food records, blood samples, and 24-h urine collections were obtained throughout the studies. The endpoints evaluated included plasma or serum concentrations of bone-specific alkaline phosphatase, osteocalcin, insulin-like growth factor-I (IGFI), IGF binding protein-3 (IGFBP3), and urine concentrations of deoxypyridinoline cross-links and carboxy-terminal telopeptide of type I collagen. In premenopausal women, IGFI and IGFBP3 concentrations were increased by the low-iso diet, and deoxypyridinoline cross-links was increased by both the low- and high-iso diets during certain phases of the menstrual cycle. In postmenopausal women, bone-specific alkaline phosphatase was decreased by both the low- and high-iso diets, and there were trends toward decreased osteocalcin, IGFI, and IGFBP3 concentrations with increasing isoflavone consumption. Although soy isoflavones do affect markers of bone turnover, the changes observed were of small magnitude and not likely to be clinically relevant. These data do not support the hypothesis that dietary isoflavones per se exert beneficial effects on bone turnover in women.     

植物雌激素对血压的影响

目的研究大豆饮食中所含的植物雌激素对健康人血压、血脂谱的影响。方法213名健康受试者(男性108人,绝经后女性105人),年龄50-75岁,随机、双盲接受特定大豆蛋白饮食(试验组)或酪蛋白安慰剂(安慰剂组)干预,为期3个月。建立多变量模型以评价治疗效果。结果饮食干预后,仅在试验组受试者尿液中植物雌激素含量增高。试验组血压较安慰剂组下降明显[收缩压(-7.5±1.2)mm Hg比(-3.6±1.1)mm Hg,P<0.01;舒张压(-4.3±0.8)mm Hg比(-1.9±0.7)mm Hg,P<0.05;平均压(-5.5±1.0)mm Hg比(-0.9±1.0)mm Hg,P<0.008]。试验组血脂水平较安慰剂组有显著改变(P<0.001),其中试验组低密度脂蛋白胆固醇/高密度脂蛋白胆固醇比值显著下降[(-0.33±0.10) mmol/L比(0.04±0.10) mmol/L,P<0.05],甘油三酯水平也有显著下降[(-0.20±0.05)mmol/L比(-0.01±0.05)mmol/L,P<0.05],而脂蛋白(a)水平升高(±95%可信区间)[42(17-67)mg/L比4(-22-31)mg/L,P<0.05]。两组中总胆固醇和低密度脂蛋白胆固醇水平均下降,高密度脂蛋白胆固醇水平升高。副作用的发生率两组相似,并且都没有观察到男性激素水平发生改变。结论在正常血压男性和绝经后女性人群中,大豆饮食对血压和血脂水平有改善作用。     

Decreased circulating levels of tumor necrosis factor-alpha in postmenopausal women during consumption of soy-containing isoflavones

CONTEXT: TNF-alpha is a key mediator of inflammatory responses and may play a pivotal role in the development of cancer and in bone resorption. OBJECTIVE: This study determined the effect of soy rich in isoflavones on levels of TNF-alpha. DESIGN: Twelve postmenopausal women ingested a 36-oz portion of soymilk containing isoflavones daily for 16 wk and provided fasting blood samples multiple times before, during, and after soy consumption for the analyses of cytokines and monocyte content. RESULTS: Compared with prediet levels (36.3 +/- 14.0 pg/ml), serum levels of TNF-alpha decreased by 25.1% (27.2 +/- 10.3 pg/ml; P < 0.01) as early as 2 wk after soy consumption and by 66.7% (11.6 +/- 5.3 pg/ml; P < 0.01) 10 wk after soy consumption and recovered to the prediet levels 4 wk after the termination of soy consumption (38.6 +/- 19.6 pg/ml; P = 0.66). A similar decrease of up to 56.6 and 14.4% was found for serum IL-1alpha and the mean percentage of blood monocytes during soy consumption, respectively, but not for IL-6. In cultures of monocytes or whole blood from postmenopausal women, soy isoflavones (genistein and daidzein, 10-1000 nm), tamoxifen (10-1000 nm), or 17beta-estradiol (0.1-10 nm) inhibited lipopolysaccharide (1 microg/ml)-induced TNF-alpha production by up to 55.8%. CONCLUSIONS: Isoflavones may be the active components in soy responsible for the decrease of TNF-alpha found in postmenopausal women during a soy diet. This antiinflammatory effect of the isoflavones may be important in immune modulation and the prevention of bone loss and cancer.     

The effect of growth hormone (GH) therapy on urinary pyridinoline cross-links in GH-deficient adults

OBJECTIVE: The aim was to study the effect of growth hormone (GH) on new markers of bone resorption (fasting urinary excretion of pyridinium cross-links (pyridinoline and deoxypyridinoline)) in GH-deficient adults. DESIGN: Randomized, double-blind, placebo-controlled cross-over study. The treatment periods (GH 2 IU/m2 subcutaneously, or placebo daily for 4 months) were separated by a 4-month washout period. PATIENTS: Twenty GH-deficient adults (aged 18-39). MEASUREMENTS: Blood and fasting urine samples were collected at the end of each 4-month treatment period. Plasma bone Gla protein was measured by radioimmunoassay and urine pyridinoline and deoxypyridinoline were measured by spectrofluorometry after high performance liquid chromatography and corrected for urinary creatinine. RESULTS: GH increased fasting urinary excretion of pyridinoline (287 +/- 123%, P less than 0.001) and deoxypyridinoline (313 +/- 140%, P less than 0.001). The GH-induced increment in these parameters correlated with the increase seen in plasma bone Gla protein (r = 0.83-0.86, P less than 0.001). CONCLUSION: Four months of GH substitution in GH-deficient adults increases bone resorption as well as bone formation. The effect on bone mass has yet to be assessed.     

Effect of menopause and hormone replacement therapy on urinary excretion of pyridinium cross-links: a longitudinal and cross-sectional study

OBJECTIVE: To study longitudinally the effect of the menopause and hormone replacement therapy on the new markers of bone resorption: urinary excretion of pyridinoline and deoxypyridinoline. DESIGN AND PATIENTS: Urinary pyridinoline and deoxypyridinoline were measured every 3 months for 2-3 years in 15 healthy women aged 45-54 years. Nine remained premenopausal and six became post-menopausal during the study. Urinary pyridinoline and deoxypyridinoline were also measured before and after 3 months of either placebo or hormone replacement therapy in 65 post-menopausal women, aged 45-54 years, who were participating in a double-blind study. MEASUREMENTS: Urinary pyridinoline and deoxypyridinoline were measured in fasting urine samples by spectrofluorometry after high performance liquid chromatography and corrected for creatinine excretion. RESULTS: Urinary pyridinoline and deoxypyridinoline remained almost constant during the premenopausal period. Both started to increase 6 months after the last menstrual bleeding and the mean post-menopausal values were 30-50% higher than the premenopausal values in the same subjects (values in nmol/mmol creatinine given as mean +/- SEM: urinary pyridinoline (premenopausal) = 29 +/- 2 vs urinary pyridinoline (post-menopausal) = 38 +/- 6, P < 0.05; urinary deoxypyridinoline (premenopausal) = 8 +/- 1 vs urinary deoxypyridinoline (post-menopausal) = 12 +/- 1, P < 0.05). Three months of post-menopausal hormone replacement therapy decreased (P < 0.001) both to premenopausal levels. CONCLUSION: Urinary pyridinoline and deoxypyridinoline, new markers of bone resorption, remain fairly constant in the years before the menopause and start to increase about 6 months after the last menstrual bleeding. This increase is reversed by hormone replacement therapy.     

Effects of the phytoestrogen genistein on the circulating soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin system in early postmenopausal women

We investigated the serum levels of both receptor activator of nuclear factor kappaB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) in postmenopausal healthy women after a 1-yr therapy with genistein, (n = 30; 54 mg/d), hormone replacement therapy (n = 30; 1 mg/d 17beta-estradiol combined with norethisterone acetate) and placebo (n = 30). By comparison with placebo, the soluble RANKL (sRANKL)/OPG ratio was lower in the genistein group (-69 +/- 7%; P < 0.01 vs. placebo 81 +/- 24%) and in hormone replacement therapy-treated women (-11 +/- 2%; P < 0.01 vs. placebo). A positive correlation (r = 0.63; P < 0.01) was found between 1-yr percentage change in sRANKL/OPG ratio and 1-yr change in urinary deoxypyridinoline, a bone resorption marker. A negative correlation was observed between 1-yr percentage change in sRANKL/OPG ratio and 1-yr change in femoral neck bone mineral density (r = -0.7; P < 0.01). Our findings suggest that the sRANKL-OPG system may mediate the beneficial effects of genistein on bone remodeling in postmenopausal women.     

Potassium citrate prevents increased urine calcium excretion and bone resorption induced by a high sodium chloride diet

The amount of sodium chloride in the diet of industrialized nations far exceeds physiological requirements. The impact of abundant dietary salt on skeletal health has yet to be established, but is potentially detrimental through increased urinary calcium losses. We examined the effect of increased dietary sodium chloride on urine calcium excretion and bone turnover markers in postmenopausal women and, further, whether potassium citrate attenuates the effects of increased dietary salt. Postmenopausal women (n = 60) were adapted to a low-salt (87 mmol/d sodium) diet for 3 wk, then randomized to a high-salt (225 mmol/d sodium) diet plus potassium citrate (90 mmol/d) or a high-salt diet plus placebo for 4 wk. Urine calcium, urine N-telopeptide, urine cAMP, serum osteocalcin, and fasting serum PTH were measured at the end of the low- and high-salt diets. On the high salt plus placebo diet, urine calcium increased 42 +/- 12 mg/d (mean +/- SEM), but decreased 8 +/- 14 mg/d in the high salt plus potassium citrate group (P = 0.008, potassium citrate vs. placebo, unpaired t test). N-telopeptide increased 6.4 +/- 1.4 nanomoles bone collagen equivalents per millimole creatinine in the high salt plus placebo group and 2.0 +/- 1.7 nanomoles bone collagen equivalents per millimole creatinine in the high salt plus potassium citrate group (P < 0.05, potassium citrate vs. placebo, unpaired t test). Osteocalcin, PTH, and cAMP were not significantly altered. The addition of oral potassium citrate to a high-salt diet prevented the increased excretion of urine calcium and the bone resorption marker caused by a high salt intake. Increased intake of dietary sources of potassium alkaline salts, namely fruit and vegetables, may be beneficial for postmenopausal women at risk for osteoporosis, particularly those consuming a diet generous in sodium chloride.     

Isoflavones improve vascular reactivity in post-menopausal women with hypercholesterolemia

This randomized clinical trial was designed to assess the effects of dietary isoflavones on vascular reactivity, lipid levels, and markers of inflammation in post-menopausal women. Epidemiological studies have revealed that populations consuming large amounts of soy protein have lower cardiovascular morbidity and mortality. The benefits of soy protein may be due to its hypolipidemic effects; its anti-oxidant properties; its high content of L-arginine; and/or or its phytoestrogen content. Two putative mediators of the effects of soy protein are the isoflavones genistein and daidzein. Forty post-menopausal, hypercholesterolemic women who did not take estrogen replacement therapy were recruited for this study of isoflavone supplementation. Baseline flow-mediated vasodilation and response to nitroglycerin were measured, along with urinary isoflavone and nitrite/nitrate levels and serum lipids. After 6 weeks of 90 mg of isoflavones daily versus placebo, women receiving isoflavones demonstrated improved responsiveness to nitroglycerin, an assessment of endothelium-independent vasodilation, with an effect size (percentage points change from baseline) of 7.2 +/- 1.9 versus 1.2 +/- 1.3; p = 0.01. There was a trend towards improvement of flow-mediated vasodilation, which is an endothelium-dependent response (effect size: 3.4 +/- 2.0% versus -0.6 +/- 1.7%; p = 0.12). Lipid levels were unchanged after isoflavone treatment. In conclusion, dietary isoflavones may have cardiovascular benefit in the form of improved vascular reactivity, but not by lowering cholesterol, for women who do not take estrogen replacement therapy.     

Soy isoflavones have a favorable effect on bone loss in Chinese postmenopausal women with lower bone mass: a double-blind, randomized, controlled trial

Animal studies have shown that soy isoflavones have an effect in preventing estrogen-related bone loss, but few data are available in humans, especially in the Asian populations. This double-blind, placebo-controlled, randomized trial examines the effects of soy isoflavones on bone loss in postmenopausal Chinese women, aged 48-62 yr. Two hundred and three eligible subjects were randomly assigned to three treatment groups with daily doses of placebo (1 g starch; n = 67), mid-dose (0.5 g starch, 0.5 g soy extracts, and approximately 40 mg isoflavones; n = 68), and high dose (1.0 g soy extracts and approximately 80 mg isoflavones; n = 68). All were given 12.5 mmol (500 mg) calcium and 125 IU vitamin D(3). Bone mineral density (BMD) and bone mineral content (BMC) of the whole body, spine, and hip were measured using dual energy x-ray absorptiometry at baseline and 1 yr post treatment. Both univariate and multivariate analyses showed that women in the high dose group had mild, but statistically significantly, higher favorable change rate in BMC at the total hip and trochanter (P < 0.05) compared with the placebo and mid-dose groups, even after further adjustments for the potential confounding factors. Further stratified analyses revealed that the positive effects of soy isoflavone supplementation were observed only among women with lower initial baseline BMC (median or less). In conclusion, soy isoflavones have a mild, but significant, independent effect on the maintenance of hip BMC in postmenopausal women with low initial bone mass.     

High dietary phytoestrogen intake is associated with higher bone mineral density in postmenopausal but not premenopausal women.

Animal studies demonstrated that phytoestrogen had a protective effect against bone loss after ovariectomy. However, data on dietary phytoestrogen intake as well as its relationship with bone mineral density (BMD) in human are not available. Six hundred fifty southern Chinese women, aged 19 to 86 yr, were recruited to determine their dietary phytoestrogen intake by a food frequency questionnaire. BMDs at the lumbar spine and hip region were measured using dual energy x-ray absorptiometry. The subjects were analyzed according to various tertiles of phytoestrogen intake. Among the postmenopausal women (n = 357), significant differences in the lumbar spine (L2-4) BMD (0.820 +/- 0.145 vs. 0.771 +/- 0.131 g/cm2, P < 0.05) and Ward's triangle BMD (0.450 +/- 0.151 vs. 0.415 +/- 0.142 g/cm2; P < 0.05) were found between the highest and lowest intake of isoflavone after adjusting for age, height, weight, years since menopause, smoking, alcohol consumption, HRT usage, and daily calcium intake. Women with the highest intake of isoflavone had significantly lower levels of serum PTH (19.38 +/- 14.61 vs. 26.56 +/- 11.19 pg/ml; P < 0.05), osteocalcin (4.95 +/- 3.61 vs. 6.69 +/- 5.05 mg/liter; P = 0.05), and urinary N-telopeptide (34.18 +/- 25.31 vs. 49.66 +/- 41.00 nmol bone collagen equivalents/mmol creatinine; P < 0.05) when compared with those with the lowest intake of isoflavone. No association between dietary phytoestrogen intake and BMDs was seen in the premenopausal women with high endogenous E (n = 293). In conclusion, postmenopausal women with habitually high intake of dietary isoflavone are associated with higher BMD values at both the spine and hip region. Customarily high isoflavone intake may help to reverse the state of secondary hyperparathyroidism associated with E withdrawal and hence lower the rate of bone turnover in postmenopausal women.     

Abnormalities in circadian patterns of bone resorption and renal calcium conservation in type I osteoporosis.

We compared changes over 24 h in 15 postmenopausal normal women (mean [+/- SD] age, 64 +/- 7 yr) with those in 15 postmenopausal women with type I osteoporosis and vertebral fractures (mean age, 64 +/- 5 yr). The serum osteocalcin concentration, a sensitive index of bone formation, increased by about 5% at night in both groups. Urinary deoxypyridinoline excretion, a sensitive index of bone resorption, increased by 48% at night (P less than 0.01) in the normal women, whereas in the osteoporotic women it was 62% higher overall (P less than 0.05), and the increase persisted into the morning. At night, urinary fractional excretion of calcium decreased by 20% (P less than 0.001) in the normal women, but was unchanged in the osteoporotic women; this circadian pattern differed between groups (P less than 0.05). The serum ionized calcium concentration did not change at night in either group. There was a trend (P = 0.07) for blunting of the nocturnal increase in the serum intact PTH level in osteoporotic women. Thus, the nocturnal serum ionized calcium level is maintained by decreased urinary calcium excretion and increased bone resorption in postmenopausal normal women, but almost entirely by increased resorption in postmenopausal osteoporotic women. This greater dependence on bone resorption during the nocturnal fast may account in part for the greater bone loss in osteoporotic women.     

Dietary soy has both beneficial and potentially adverse cardiovascular effects: a placebo-controlled study in men and postmenopausal women.

To address the cardiovascular effects of dietary soy containing phytoestrogens, we measured blood pressure (BP), lipids, vascular function (systemic arterial compliance and pulse wave velocity), and endothelial function (flow-mediated vasodilation) in a randomized, double-blind trial. Two hundred thirteen healthy subjects (108 men and 105 postmenopausal women), 50-75 yr old, received either soy protein isolate (40 g soy protein, 118 mg isoflavones) or casein placebo for 3 months. There were 34 withdrawals (16%), with 179 subjects (96 men and 83 women) completing the protocol. After intervention in the soy group, compared with casein placebo, urinary phytoestrogens increased, accompanied by a significant fall in BP reflected by the BP model (P < 0.01) encompassing mean change (+/-SEM) in systolic (-7.5 +/- 1.2 vs. -3.6 +/- 1.1 mm Hg, P < 0.05), diastolic (-4.3 +/- 0.8 vs. -1.9 +/- 0.7 mm Hg, P < 0.05), and mean BP (-5.5 +/- 1 vs. -0.9 +/- 1 mm Hg, P < 0.008). In the lipid model, soy induced greater changes, compared with placebo (P < 0.001). On individual analysis, significant contributors included a reduction in the low- to high-density lipoprotein ratio (-0.33 +/- 0.1 vs. 0.04 +/- 0.1 mmol/L, P < 0.05) and triglycerides (-0.2 +/- 0.05 vs. -0.01 +/- 0.05 mol/L, P < 0.05) and an increase in Lp(a) lipoprotein (+/- 95% confidence interval) [42 (range, 17-67) vs. 4 (range, -22-31) mg/L, P < 0.05], whereas total, low-density lipoprotein, and high-density lipoprotein cholesterol improved in both groups; but no treatment effect was demonstrated. The arterial functional model demonstrated no difference between groups; although again, overall function improved in both groups. On individual analysis, peripheral PWV (reflecting peripheral vascular resistance) improved with soy (P < 0.01), whereas flow-mediated vasodilation (reflecting endothelial function) declined (in males only), compared with casein placebo (P < 0.02). No effect of treatment on the hypothalamic-pituitary-gonadal axis was noted in males or females. In normotensive men and postmenopausal women, soy improved BP and lipids but, overall, did not improve vascular function. Potential adverse effects were noted, with a decline in endothelial function (in males only) and an increase in Lp(a). Further research in hypertensive and hyperlipidemic populations is needed.     

Soy protein, isoflavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee

Soy protein and isoflavones (phytoestrogens) have gained considerable attention for their potential role in improving risk factors for cardiovascular disease. This scientific advisory assesses the more recent work published on soy protein and its component isoflavones. In the majority of 22 randomized trials, isolated soy protein with isoflavones, as compared with milk or other proteins, decreased LDL cholesterol concentrations; the average effect was approximately 3%. This reduction is very small relative to the large amount of soy protein tested in these studies, averaging 50 g, about half the usual total daily protein intake. No significant effects on HDL cholesterol, triglycerides, lipoprotein(a), or blood pressure were evident. Among 19 studies of soy isoflavones, the average effect on LDL cholesterol and other lipid risk factors was nil. Soy protein and isoflavones have not been shown to lessen vasomotor symptoms of menopause, and results are mixed with regard to soy's ability to slow postmenopausal bone loss. The efficacy and safety of soy isoflavones for preventing or treating cancer of the breast, endometrium, and prostate are not established; evidence from clinical trials is meager and cautionary with regard to a possible adverse effect. For this reason, use of isoflavone supplements in food or pills is not recommended. Thus, earlier research indicating that soy protein has clinically important favorable effects as compared with other proteins has not been confirmed. In contrast, many soy products should be beneficial to cardiovascular and overall health because of their high content of polyunsaturated fats, fiber, vitamins, and minerals and low content of saturated fat.     

The effects of dietary supplementation with isoflavones from red clover on the lipoprotein profiles of post menopausal women with mild to moderate hypercholesterolaemia

The effects of dietary isoflavone supplementation using a purified extract of red clover containing approximately biochanin A 26 mg, formononetin 16 mg, daidzein 0.5 mg and genistein 1 mg per tablet at doses of one or two tablets per day were compared to placebo in a three-period, randomised, double blind, ascending dose study in 66 post menopausal women with plasma cholesterol levels between 5.0 and 9.0 mmol/l. Each treatment period lasted 4 weeks and a further nine women received placebo for the full 12-week period. All women consumed a low isoflavone diet for 2 weeks preceding the commencement of the study and for the 12-week study period. Urinary isoflavone excretion was very low in subjects receiving placebo but increased in a dose-dependent manner during therapy with one and two of isoflavone tablets. Dietary supplementation with isoflavones did not significantly alter total plasma cholesterol, LDL cholesterol, HDL cholesterol or plasma triglyceride levels. However, inverse correlations were found between urinary genistein excretion and plasma triglyceride levels and between urinary O-DMA excretion (an isoflavone metabolite) and plasma triglyceride levels in subjects receiving one isoflavone tablet, suggesting a weak relationship between isoflavone intake and plasma triglycerides which may be influenced by individual differences in isoflavone absorption or metabolism. The results suggest that isoflavone phytoestrogens from red clover in the proportions and quantities studied do not significantly alter plasma lipids in post menopausal women with moderately elevated plasma cholesterol levels.     

Cooperative effects of isoflavones and exercise on bone and lipid metabolism in postmenopausal Japanese women: a randomized placebo-controlled trial

Cooperative effects of isoflavones and exercise on bone and lipid metabolism have been exhibited in estrogen-deficient animals; however, results from clinical trials have not been published. In this study, we determined the effects of isoflavone intake and walking and their interaction on bone and lipid metabolism in postmenopausal women over 24 weeks. The bioavailability and metabolism of isoflavones (daidzein in particular) were also examined to clarify the mechanism of their bone-protective effects in humans. One hundred twenty-eight subjects were randomly assigned to 4 groups: placebo; placebo combined with walking (3 times per week); isoflavone intake (75 mg of isoflavones conjugates per day); and isoflavone combined with walking. The subjects were classified by equol status (producers or nonproducers) as identified using production of equol from daidzein in fecal culture. Bone mineral density (BMD), body composition, and serum concentrations of isoflavones were assessed. Serum high-density lipoprotein cholesterol concentration significantly increased (6.1%, P = .03), and fat mass in the whole body significantly decreased (-4.3%, P = .0003) from the baseline in the combined intervention group. There were no significant differences in BMD between baseline and postintervention in any of the treatment groups. However, the percent changes in BMD in equol producers were -0.53% and +0.13% in the sub-whole body and total hip, respectively. This was significantly different compared with -1.35 and -1.77 for the sub-whole body and total hip, respectively, in nonproducers in the isoflavone group (P = .049 and .040, respectively). The mean serum equol concentration was significantly higher in equol producers than in nonproducers in the isoflavone groups, but not in the placebo group. The combination of isoflavones and exercise exhibited favorable effects on serum lipid and body composition of postmenopausal women. The findings of this study suggest that the preventive effects of isoflavones on bone loss depend on the individual's intestinal flora for equol production.     

Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women

The possibility that the heightened cardiovascular risk associated with the menopause can be reduced by increasing dietary isoflavone intake was tested in 17 women by measuring arterial compliance, an index of the elasticity of large arteries such as the thoracic aorta. Compliance diminishes with age and menopause. An initial 3- to 4-week run-in period and a 5-week placebo period were followed by two 5-week periods of active treatment with 40 mg and then 80 mg isoflavones derived from red clover containing genistein, daidzein, biochanin, and formononetin in 14 and 13 women, respectively, with 3 others serving as placebo controls throughout. Arterial compliance, measured by ultrasound as a pressure (carotid artery) and volume (outflow into aorta) relationship, was determined after each period; plasma lipids were measured twice during each period. Urinary output of isoflavones was also determined. Arterial compliance rose by 23% relative to that during the placebo period with the 80-mg isoflavone dose and slightly less with the 40-mg dose (mean +/- SEM: placebo, .197 +/- .015; 40 mg, .237 +/- 0.007; 80 mg, .244 +/- .014). In the three women receiving continuous placebo, compliance was .16 +/- .022, similar to that during the run-in period for the remaining subjects (.17 +/- .021) [corrected]. ANOVA showed a significant (P = < 0.001) difference between treatments; by Bonferroni multiple comparisons and by paired t test, differences were significant between placebo and 40- and 80-mg isoflavone doses (by paired t test: P = 0.039 for placebo vs. 40 mg; P = 0.018 for placebo vs. 80 mg). Plasma lipids were not significantly affected. An important cardiovascular risk factor, arterial compliance, which diminishes with menopause, was significantly improved with red clover isoflavones. As diminished compliance leads to systolic hypertension and may increase left ventricular work, the findings indicate a potential new therapeutic approach for improved cardiovascular function after menopause.