Soy isoflavones interact with calcium and contribute to blood pressure homeostasis in women: a randomized, double-blind, placebo controlled trial

Abstract

Background: Estrogens and calcium regulate vascular health but caused adverse cardiovascular events in randomized trials.

Objectives: Whether phytoestrogenic soy isoflavones modulate the physiological effects of calcium on blood pressure was explored.

Design: A double-blind, randomized study assigned 99 premenopausal women to 136.6 mg isoflavones (as aglycone equivalents) and 98 to placebo for 5 days per week for up to 2 years. Blood pressure, serum calcium and urinary excretion of daidzein (DE) and genistein (GE) were measured repeatedly before and during treatment.

Results: Isoflavones did not affect blood pressure per intake dose assignment (i.e. intention-to-treat, n = 197), but significantly affected blood pressure per measured urinary excretion of isoflavones (i.e. per protocol analysis, n = 166). Isoflavones inversely moderated calcium effects on systolic blood pressure (SBP) (interaction term β-estimates: - 3.1 for DE, - 12.86 for GE, all P < 0.05), and decreased diastolic blood pressure (DBP) (β-estimates: - 0.84 for DE, - 2.82 for GE, all P < 0.05) after controlling for calcium. The net intervention effects between the maximum and no isoflavone excretion were - 17.7 and + 13.8 mmHg changes of SBP, respectively, at serum calcium of 10.61 and 8.0 mg/dL, and about 2.6 mmHg decrease of DBP.

Conclusions: Moderation by isoflavones of the physiological effect of calcium tends to normalize SBP, and this effect is most significant when calcium concentrations are at the upper and lower limits of the physiological norm. Isoflavones decrease DBP independent of calcium levels. Further studies are needed to assess the impact of this novel micronutrient effect on blood pressure homeostasis and cardiovascular health.

Trial registration: www.clinicaltrials.gov identifier: NCT00204490.

Keywords: Blood pressure homeostasis; Daidzein; Genistein; Micronutrients; Selective estrogen receptor modulator.

Conflict of interest statement

Financial and non-financial competing interests:

All authors declare that they have no competing interests.

Figures

Figure 1:

Study design and protocol: There were 2 baseline visits (B1 & B2) 2 days apart in each one of the two screening menstrual cycles. After randomization and during supplements, follow-up visits (V1to V8) occurred every 3 menstrual cycles apart for 2 years. Subjects in each treatment arm were randomized into 3 subgroups, so the first follow-up visit was after being on supplement for either 1, 2, or 3 menstrual cycles. All study visits occurred during the luteal phase of the menstrual cycle. On each visit, subjects brought a 12-hr urine collection, provided fasting blood samples, and were measured for blood pressure, weight, and height by study nurse. Mammograms, breast magnetic resonance images, and bone density scans were acquired once before and annually after supplements coincided with a study visit.

Figure 2:

Flow diagram of a blinded randomized trial comparing effects of soy isoflavones and placebo on blood pressure showing the enrollment of 30- to 42-year-old female subjects, allocation to treatment, follow-up for up to 2 years, and data analysis, as described [33].

Figure 3:

Probing the interactive effects of isoflavone(s) and calcium on systolic blood pressure (SBP) (using Model 3 of Table 4 as an example) by the Johnson-Neyman technique [35]. Panels A-B are plots of simple slopes for focal predictor isoflavones and SBP as a function of serum calcium at the 10th (Low Ca2+), 50th (Median Ca2+), and 90th (High Ca2+) percentiles of values found in our study samples. Panels C to F show the regions of significance and 95% confidence bands for the regression slope estimates for the conditional relation between SBP and isoflavone concentrations as a function of serum calcium. The dashed vertical lines (----- in panels C-F) indicate calcium thresholds separating regions of statistical significances. Panels A & C for daidzein (DE) as predictor; B & D for genistein (GE); E for sum excretion (DE + GE); and F for difference in excretion (DE – GE). Note that the lengths of all graph lines correspond to ranges of data found in our study samples. Simple slopes for DE + GE and DE – GE are not shown.