Soy Isoflavones for Reducing Bone Loss Study: effects of a 3-year trial on hormones, adverse events, and endometrial thickness in postmenopausal women

Abstract

Objective: This study aims to assess the overall safety and potential endometrium-stimulating effects of soy isoflavone tablets consumed (3 y) by postmenopausal women and to determine endometrial thickness response to treatment among compliant women, taking into account hormone concentrations and other hypothesized modifying factors.

Methods: We randomized healthy postmenopausal women (aged 45.8-65.0 y) to placebo control or two doses (80 or 120 mg/d) of soy isoflavones at two sites. We used intent-to-treat analysis (N = 224) and compliant analysis (>95%; N = 208) to assess circulating hormone concentrations, adverse events, and endometrial thickness (via transvaginal ultrasound).

Results: Median values for endometrial thickness (mm) declined from baseline through 36 months. Nonparametric analysis of variance for treatment differences among groups showed no differences in absolute (or percentage of change) endometrial thickness (χ(2) P ranged from 0.12 to 0.69) or in circulating hormones at any time point. A greater number of adverse events in the genitourinary system (P = 0.005) were noted in the 80 mg/day group compared with the 120 mg/day group, whereas other systems showed no treatment effects. The model predicting endometrial thickness response (using natural logarithm) to treatment among compliant women across time points was significant (P ≤ 0.0001), indicating that estrogen exposure (P = 0.0013), plasma 17β-estradiol (P = 0.0086), and alcohol intake (P = 0.023) contributed significantly to the response. Neither the 80 mg/day dose (P = 0.57) nor the 120 mg/day dose (P = 0.43) exerted an effect on endometrial thickness across time.

Conclusions: Our randomized controlled trial verifies the long-term overall safety of soy isoflavone tablet intake by postmenopausal women who display excellent compliance. We find no evidence of treatment effects on endometrial thickness, adverse events, or circulating hormone concentrations, most notably thyroid function, across a 3-year period.

Trial registration: ClinicalTrials.gov NCT00043745.

Figure 1

Study participant CONSORT (Consolidated Standards of Reporting Trials) diagram ^a Altogether, 31 women were lost to follow-up (LTFU; 2 at Iowa State University [ISU], 29 at University of California at Davis [UCD]). Diagram indicates the last time point [baseline (base) or 6, 12, 24 mo] at which we collected data for each woman who was LTFU and reasons for discontinuance. ^b Eleven women at UCD had thickened endometria [(determined by transvaginal ultrasound (TVU)] and thus did not meet inclusion criterion (≤5 mm). BMD, bone mineral density ^c Eight women discontinued treatment but completed trial (1 at ISU, 7 at UCD)

Figure 2. Endometrial Thickness (mm): Iowa State University (ISU, left panel); University of California-Davis (UCD, right panel)

Endometrial thickness decreased for each site during treatment. Graphical display and statistical analysis remained separate for each geographic site because endometrial thickness values between sites were statistically different (p≤0.0001) at each time point, due to differences in ultrasound equipment. Median values (mm) for ISU and UCD, respectively: Baseline – 1.50 & 2.60; 12 mo – 1.30 & 2.50; 36 mo – 1.10 & 1.90. Nonparametric ANOVA for treatment differences (absolute) among groups showed no differences at any time point (Chi-Square p values ranged from 0.12 to 0.69). Likewise, nonparametric ANOVA indicated that treatment had no effect on percentage change at 12 or 36 mo (Chi-Square p value=0.46 and 0.28, respectively). Tests for parallel profiles (based on Wilks’ lambda criterion) to determine consistency of treatment differences across all time points revealed no treatment by time interaction for endometrial thickness at either ISU (p=0.41) or UCD (p=0.70), indicating no treatment effect. [Table: see text]