3,3 Diindolylmethane (DIM) is a major hydrolysis product of the dietary glucosinolate,

indole-3 carbinol (I3C), derived from Brassica (cruciferous) family vegetables such as broccoli, bok choy, cabbage, cauliflower, collards, kale, Brussels sprouts, and kohlrabi. I3C, alone, is very unstable and in acidic conditions is converted to several compounds with biological effects. Nearly 10-20 percent of I3C is converted to DIM, which is classified as a phytoestrogen and most well-known as an estrogen receptor antagonist, thereby theoretically helping to reduce the risk of estrogen-driven cancers. However, in vitro studies have also shown DIM to possess anti-proliferative and anti-cancer activities in various cancer cells including prostate, breast, endometrial, colorectal and pancreatic cancers.

Estrogen dominance continues to be a concern, leading to hormone imbalances in both men and women. As a result, estrogen dominance can be a root problem underlying various health concerns such as menstrual abnormalities, reproductive problems in both men and women, sexual dysfunction, insomnia, fatigue, mood and cognitive difficulties, poor digestion, compromised cardiovascular health, and low thyroid function. Estrogen dominance can occur from internal scenarios such as poor liver detoxification capabilities or obesity, as well as external factors such as contraceptive use, commercial meat and dairy intake, use of plastics, and a high toxin load. Estrogen concentrations in soil and water have been rapidly increasing, leading to the rise in estrogen-dominated health problems.

In light of this dilemma, there is a deliberate focus on supporting estrogen detoxification, especially among functional medicine practitioners who are well aware of the potential long-term health effects of hormone imbalances. DIM is one potential choice to help support the reduction of estrogen’s negative effects.

The development and progression of estrogen-driven cancers, including both breast and prostate cancers, usually involves the action of 17-beta-estradiol (E2) upon estrogen receptors including ERβ in the prostate epithelium. E2 promotes cell proliferation. DIM may help modulate the impact of estrogen in numerous ways. First, it may support the conversion of E2 into a healthier form, 2-hydroxyestrone (2-OHE), with anti-estrogenic and anti-proliferative properties. Second, DIM selectively modulates gene activity via its action on estrogen receptors. For example, in an in vitro study, researchers found DIM depressed mRNA expression of ER-α in MCF-7 breast cancer cells which may help curtail metastasis and cell proliferation. Another in vitro assay supported these findings when treatment with DIM suppressed E2, triclosan, and BPA-induced cell proliferation, epithelial-mesenchymal transition (EMT), cell migration, and invasion of MCF-7 breast cancer cells.

Not only does DIM work directly on estrogen metabolism and receptor activity, but it also works to stimulate cellular detoxification pathways, which theoretically may indirectly help support the prevention of various cancers. According to researchers, DIM may help modulate aryl hydrocarbon receptor (AhR), which promotes transcription of genes that stimulate the expression of detoxification enzymes from the phase I cytochrome P450 (CYP) family. This group of enzymes is important for regulating the body’s inflammatory response pathways, acts as antioxidants, and enhances the excretion of genotoxins. Inflammation, oxidation, and genotoxins are activities involved in cancer initiation and progression. CYP enzymes also help regulate steroid hormone metabolism and are involved in converting estrogen metabolites to their safer forms.

In a randomized placebo-controlled trial of 98 women that sought to determine the activity and safety of combined use of DIM with tamoxifen, researchers found that daily treatment with DIM in women taking tamoxifen for breast cancer promoted favorable changes in estrogen metabolism and increased circulating levels of sex hormone-binding globulin (SHBG). DIM increased the ratio of anti-tumorigenic estrogen (2-hydroxyestrone) to pro-tumorigenic estrogen (16α-hydroxyestrone).

DIM may not only be helpful for women at risk for estrogen-dominant cancers, but possibly also for men at risk for prostate cancer. According to researchers, evidence suggests that 17beta-estradiol (E2) contributes to the risk of prostate cancer. As men age, testosterone levels decrease, but estrogen levels remain relatively unchanged, leading naturally to estrogen-dominance – a phenomenon that promotes carcinogenesis, evidenced by the lower prevalence of prostate cancer in men who retain higher ratios of testosterone to estrogen. In a study seeking to discover the effects of DIM on sperm parameters, histological structures of testicular tissues, blood testosterone, and E2 in 38 male Sprague Dawley rats, treatment with lower doses of DIM (10 mg kg^-1) showed anti-estrogenic activity and increased levels of antioxidant malondialdehyde in testes, but higher doses (50 mg kg^-1) led to histological degeneration of testicular tissues and apoptosis in a dose-dependent manner.

Prostate cancer is more commonly viewed in light of androgens, testosterone and DHT. According to one review, both in vitro and in vivo studies show DIM has an anti-androgen effect which downregulates androgen receptors and prostate-specific antigen (PSA). Researchers suggest its action has been linked to its ability to inhibit DHT stimulation of DNA synthesis and endogenous PSA transcription while suppressing androgen receptor translocation into the nucleus. DIM was also shown to arrest the cell cycle in androgen-sensitive cells which limited the ability for cells to proliferate. In some rat studies in which rats were injected with prostate cancer cells, DIM reduced tumor development by 50 percent, compared to controls.

It seems that the common dietary advice to eat cruciferous vegetables every day is not unfounded and, perhaps, should be emphasized even more as we experience the effects of estrogen dominance. However, for some individuals who are at higher risks for estrogen dominant cancers or health effects, supplemental DIM may provide some extra support and relief, along with dietary and lifestyle interventions to help dim the effects of estrogen.