Effect of Diindolylmethane on Estrogen-related Hormones, Metabolites and Tamoxifen Metabolism: Results of a Randomized, Placebo-controlled Trial

Abstract

Dietary supplement use is high among breast cancer survivors. One compound natural to cruciferous vegetables, diindolylmethane (DIM), is among the supplements commonly used. This bioactive compound has significant experimental evidence for bioactivity in breast chemoprevention. Sparse evidence in the form of well-designed human clinical trials exist to test its efficacy or safety. Methods: In this double-blind placebo-controlled study women taking tamoxifen for breast cancer primary or tertiary prevention were randomly assigned to receive 150 mg DIM (BioResponse(BR)-DIM) twice daily or a placebo for a minimum period of 12 months. Primary outcome was change in urinary estrogen metabolites 2-hydroxyestrone and 16α-hydroxyestrone (baseline to 6 weeks, 6 and 12 months). Secondary endpoints included breast density by mammogram and fat:water ratio MRI (baseline to 12 months) and serum estrogens (baseline to 6, 12 months). Safety data were also evaluated, including tamoxifen metabolites. Results: Adherence to study pills was >91% by pill count and urinary DIM metabolite assessment. In participants assigned DIM there was a significant and sustained shift in urinary estrogen metabolism favoring a higher 2-OH:16α-OH ratio; sex hormone binding globulin (SHBG) was also increased. No change in breast density was demonstrated. Safety analysis showed no appreciable differences in adverse events by treatment arm; however, tamoxifen metabolism for the parent compound as well as endoxifen and 4-OH endoxifen were appreciably reduced in women assigned to the DIM arm. Conclusions In this first large study of DIM in the setting of breast cancer chemoprevention, a favorable shift in estrogen metabolism and SHBG was demonstrated. However, the reduction in tamoxifen metabolites raises concern regarding the potential interaction between DIM and tamoxifen, an area in need of continued research. Impact Given the widespread and generally unsupported use of dietary supplementation by breast cancer survivors, these data will help to inform the use of DIM as a dietary supplement for breast cancer patients receiving tamoxifen.