A recent study found that 3,3’-diindolylmethane, a supplement derived from cruciferous vegetables, significantly altered urinary estrogen metabolite levels in postmenopausal women using transdermal estradiol patches.
The findings suggest a potential drug-supplement interaction that could affect the pharmacokinetics of menopausal hormone therapy (MHT).
Investigators analyzed data from 1,458 postmenopausal women using transdermal estradiol (E2) patches, of whom 108 reported concurrent diindolylmethane (DIM) use. Compared to non-users, DIM users had significantly different urinary estrogen profiles, including lower estrone and estriol levels, and higher concentrations of 2-hydroxyestrone and 2-hydroxyestradiol.
After adjusting for age, body mass index, estradiol patch dose, and urinary creatinine, regression models confirmed that DIM use was significantly associated with differences in six of ten measured estrogen metabolites. Estrone concentrations were lower among DIM users (median 6.4 ng/mg-Cr vs 8.3 ng/mg-Cr; P = .002), while 2-hydroxyestrone was higher (median 3.92 ng/mg-Cr vs 3.16 ng/mg-Cr; P = .002). Total urinary estrogen levels were also reduced (median 17.95 ng/mg-Cr vs 20.90 ng/mg-Cr; P = .044).
The study suggests DIM’s modulation of estrogen metabolism occurs through its induction of cytochrome P450 enzymes, particularly CYP1A1 and CYP3A4. These enzymes influence how estrogen is metabolized, which may alter the overall estrogenic impact of MHT. The prescribing information for estradiol patches currently includes a warning for CYP3A4 inducers, such as St. John’s wort, but does not mention DIM.
Mark S. Newman, MS, president and CEO of Precision Analytical, Inc. in McMinnville, Oregon, co-authored the study with Jaclyn Smeaton, ND. They stated, “Postmenopausal women who are prescribed transdermal E2 patch therapy who choose to concurrently use a DIM supplement may have unexpected changes in their urinary estrogen profiles.”
The study used a validated gas chromatography–tandem mass spectrometry method to analyze four samples collected combined to represent a 24-hour time period. Although DIM dosage and adherence data were not available, the metabolite differences remained consistent across E2 patch doses, suggesting a measurable effect independent of DIM formulation.
Investigators emphasized that while these metabolic shifts were statistically significant, their clinical implications remain unclear. Prior studies have suggested that increasing the 2-hydroxyestrone to 16-hydroxyestrone ratio, which was higher among DIM users (median 16.57 vs 8.24; P < .001), may be associated with lower breast cancer risk, though no consensus has been reached regarding clinically meaningful thresholds.
The authors recommended that providers routinely ask patients on MHT about supplement use, specifically DIM or its precursor indole-3-carbinol, and consider whether dose adjustments to hormone therapy may be necessary. Future studies are needed to determine whether the observed metabolic changes affect symptom relief, bone mineral density, or other therapeutic endpoints.
Full disclosures can be found in the published study.
Source: Menopause