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

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 (chi(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 17 beta-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.