Diindolylmethane (DIM) Interactions with Hormones

Estrogen

3,3'-diindolylmethane (DIM) has been noted to activate both the alpha subset of the estrogen receptor (ERα) and the beta subset (ERβ), with DIM promoting cellular growth via ERα not due to being a direct ligand while increased signalling via ERβ (15μM) also seems to be mediated indirectly.

Activation of ERα may be dependent on the cell type, as similar concentrations (10-15μM; the lower concentration being proposed to be attained via a cruciferous rich diet) have shown efficacy in acting on this receptor in MCF7 and T47D breast cancer cells yet not MDA-MB-231 or HeLa cells, or may be due to sensitivity, as even in responsive cells higher concentrations (50μM) fail to cause a response. The indirect activation is known to be mediated predominately via activation of PKA which then activates MAPK and CREB.

DIM can activate both subsets of the estrogen receptor (in tested breast cancer cells) in an indirect manner, secondary to activating a protein known as PKA. At this moment in time these effects have only been observed in cancerous cells, and it may be exclusive to low (dietary) concentrations of DIM
The higher concentration of DIM seems to induce AhR responsive genes in breast cancer cells (CYP1A1 and CYP1B1) suggesting a differing mechanisms dependent on concentration. Activation of AhR per se induces production of some of these Phase I enzymes which is a mechanism of estrogenicity (via increasing aromatase activity) seen with a few environmental estrogens but due to the lesser affinity of DIM towards the AhR than select environmental estrogens (PCBs, Dioxins, and PAHs) combination of the two may result in less overall estrogenicity relative to the environmental estrogens alone.

Activation of AhR is in and of itself proestrogenic via increasing the expression of the aromatase enzyme (CYP1A1), but due to a lesser competitive activation from DIM it seems that when it is taken alongside more potent ligands found in the environment (ex. PAHs from smoked meat products) may result in less net estrogenicity
DIM has been implicated in modifying preexisting estrogen steroids into other metabolites. The process of 2-hydroxylation, likely secondary to AhR activation, may increase the ratio of 2-hydroxyestrone to 16α-hydroxyestrone which is thought to be a less estrogenic profile of estrogen steroids.The processes of 4-hydroxylation and 16-hydroxylation do not appear significantly affected.

Indole-3-carbinol has been noted to induce 2-hydroxyestrone secondary to an increase in the process of 2-hydroxylation and oral supplementation of DIM (108mg) in women with histories of early stage breast cancer has been noted to increase urinary 2-hydroxyestrone concentrations (alongside a nonsignificant increase of the 2-hydroxyestrone to 16α-hydroxyestrone ratio. In rats given dietary I3C for a prolonged period of time 200-1,000ppm appeared to be effective in increasing 2-hydroxylation of estradiol with efficacy peaking to a near double around 600-1,000ppm (17.6-36.3mg/kg), translating to around 3-6mg/kg in an adult human.

Secondary to activating AhR activity, it is possible for DIM to increase the process of 2-hydroxylation and cause a shift in preexisting estrogen metabolites to a profile which is seen as less estrogenic; evidence for this has been seen in women given low dose supplements.