Directions: As a dietary supplement, take one softgel per day with a meal, or as directed by your health care practitioner.
Storage: Store at room temperature, out of reach of children
Does Not Contain: Wheat, gluten, soy, dairy, fish, shellfish, peanuts, tree nuts, egg, GMOs, artificial colors, artificial sweeteners, or artificial preservatives.
Diindolylmethane (DIM) is derived from the primary plant indole found in cruciferous vegetables, known as indole-3-carbinol (I3C). Mastication, cooking, and other actions activate the enzyme myrosinase to convert I3C to DIM. Stomach acid additionally contributes to the formation of DIM, which is a more stable compound than I3C.1,2
Research identifies beneficial actions of DIM on estrogen metabolism and associated conditions. Estrogen Metabolism Estrogen balance plays an important role in health, and disturbances of this hormone are associated with polycystic ovary syndrome, endometriosis, osteoporosis, Alzheimer’s disease, autoimmune disorders, male hypogonadism, schizophrenia, and breast, ovarian, and other estrogen-related cancers. Estrogen is involved in glucose homeostasis, lipid homeostasis, bone metabolism, brain function, follicular growth, skeletal growth, and ovulation.
Estrogen biosynthesis involves the aromatization of androgen into estrogen.3,4 The main circulating estrogen is 17 beta-estradiol (E2), which is produced in the ovaries as a circulating hormone. In postmenopausal females and those without ovaries, E2 is synthesized in extragonadal sites to act locally as a paracrine, with the aromatization of androgens to estrogens playing a more significant role.
Estrogen metabolism involves hydroxylation at the A-ring or D-ring by cytochrome P450 isoforms. This may occur on the C2 or C4 position in the A-ring or in the 16-alpha position in the D-ring, producing the metabolites 2-hydroxy estrone/estradiol, 4-hydroxy estrone/estradiol, and 2-hydroxy estrone/estradiol.5-11 The specific cytochrome P450 enzyme promotes which metabolite is produced.
For example, CYP1B1 converts E2 to 16 alpha-hydroxy estradiol, whereas CYP1A1 converts it to 2-hydroxyestradiol. Both enzymes can also convert E1 and E2 into 4-hydroxy metabolites. The different metabolites have different functions in the body, and a balance is required for optimal health.
The 16-alpha hydroxy estrone has a high capacity to bind to estrogen receptors and produce estrogenic effects, and 2-hydroxyestrone has little to no affinity for the estrogen receptor. The 4-hydroxy estrogens have the potential to cause DNA damage, generate mutations, and create oxidative damage. The lower affinity and subsequent decrease of bioavailable estrogens may be why the two-pathway metabolites relate to a lower risk of breast cancer.
However, the ratio of metabolites and the clearance of estrogens may matter more than the level of the individual metabolites.6-11 Higher levels of 4-hydroxy estrogens and 16-alpha-hydroxy estrogens are associated with a higher risk of breast cancer.7 High levels of 4-hydroxy estrogens are also associated with endometriosis.12
A high 2:16 ratio (with 2 hydroxy to 16 hydroxy estrogens) is associated with reduced inflammation and a lower risk of breast cancer.8,13 Upon activation, estrogen receptors trigger pathways for cell growth, proliferation, and inflammation in addition to pre-malignant pathology. These estrogen metabolites may stimulate the synthesis of proinflammatory cytokines such as tumor necrosis factor-alpha(TNF-a).
They may also impact other conditions, including autoimmune diseases. Studies have found that higher levels of estrogen, including the hydroxylated metabolites, were significantly increased in the synovial fluid of patients with rheumatoid arthritis (RA).13-15
One study found that the 2:16 ratio in patients with RA and systemic lupus erythematosus (SLE) was more than 20 times lower than healthy subjects due to significantly lower levels of 2-hydroxy estrogens. These results were independent of steroid use and sex.16
DIM and Estrogen Metabolism Certain compounds, such as DIM, can influence estrogen metabolism to determine which metabolite is synthesized, pushing the pathways toward the more harmful or beneficial metabolites.6,17 DIM supports the synthesis of 2-hydroxyestrone, which in turn supports an increase of the 2:16 ratio without elevating the 4-hydroxy estrogens.
This is likely due to its impact on cytochromes P450 (CYP) enzymes, supporting the expression of CYP1A1 over the other enzymes.1,18 This positive impact on estrogen metabolism may also support conditions associated with higher levels of the more harmful estrogen metabolites.
In one prospective clinical trial, supplementing with 100 mg of DIM per day for a year in breast cancer gene (BRCA) carriers (with a high risk of breast cancer) was associated with a significant decline in fibroglandular tissue, whereas a control group did not experience any significant changes. Breast density is a surrogate marker for breast cancer risk.17 DIM has also been shown to promote more favorable estrogen metabolism by increasing the 2-hydroxy:16-alpha-hydroxy ratio due to increasing the 2-hydroxy pathway when used as adjunct therapy for breast cancer.19 Another trial found that DIM supplementation improved bleeding patterns in patients with endometriosis, especially when used as adjunct therapy.
This was likely due to its reduction of estradiol secretion.20 In addition to acting on estrogen, DIM may also impart anti-inflammatory effects by inhibiting TNF-α. DIM inhibits TNF-α and transforming growth factor-beta 1)–associated signaling pathways, including the activation of epithelial-mesenchymal transition, the initial step of cancer metastasis. It may also inhibit the NF-kB pathway and suppress T22/type 1 T helper 17 (Th17)-type immune reactions whIle promoting Treg differentiation.2,21-23
Recommended Use: As a dietary supplement, take one softgel per day with a meal, or as directed by your health care practitioner.
- Johnson IT. Glucosinolates: bioavailability and importance to health. Int J Vitam Nutr Res. 2002 Jan;72(1):26-31.
- McDanell R, McLean AE, Hanley AB, Heaney RK, Fenwick GR. Chemical and biological properties of indoleglucosinolates. J Agric Food Chem. 1999 Apr;47(4):1541-8.
- Grose, KR, and Bjeldanes, LF. Oligermization of indole-3-carbinol in aqueous acid. Chem Res Toxicol 1992: 5:188-193.(glucobrassicins): a review. Food Chem Toxicol. 1988 Jan;26(1):59-70. Review.
- Park JY, Shigenaga MK, Ames BN. Induction of cytochrome P4501A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin or indolo(3,2-b)carbazole is associated with oxidative DNA damage.
- Jensen-Jarolim E, Gajdzik L, Haberl I, Kraft D, Scheiner O, Graf J.Hot spices influence permeability of human intestinal epithelial monolayers. J Nutr. 1998 Mar;128(3):577-81.
- Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF. Pilot study: effect of 3,3’-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer. 2004;50(2):161-7.
- Jellinck PH, Makin HL, Sepkovic DW, Bradlow HL. Influence of indole carbinols and growth hormone on the metabolism of 4-androstenedione by rat liver microsomes. J Steroid Biochem Mol Biol. 1993 Dec;46(6):791-8
- Yoshida M, Katashima S, Ando J, Tanaka T, Uematsu F, Nakae D, Maekawa A. Dietary indole-3-carbinol promotes endometrial adenocarcinoma development in rats initiated with N-ethyl-N’-nitro-N-nitrosoguanidine, with induction of cytochrome P450s in the liver and consequent modulation of estrogen metabolism. Carcinogenesis. 2004 Nov;25(11):2257-64. Epub 2004 Jul 7.
- Shertzer HG, Sainsbury M. Intrinsic acute toxicity and hepatic enzyme inducing properties of the chemoprotectants indole-3-carbinol and 5,10-dihydroindeno[1,2-b]indole in mice. Food Chem Toxicol. 1991 Apr;29(4):237-42.
- Hien T. Le, Charlene M. Schaldach, Gary L. Firestone, and Leonard F. Bjeldanes. Plant-derived 3,3_-Diindolylmethane Is a Strong Androgen Antagonist in Human Prostate Cancer Cells. Journal of Biological Chemistry Vol. 278, No. 23, Issue of June 6, pp. 21136-21145, 2003.
- Nachshon-Kedmi M, Yannai S, Fares FA Induction of apoptosis in human prostate cancer cell line, PC3, by 3,3’-diindolylmethane through the mitochondrial pathway. Br J Cancer. 2004 Oct 4;91(7):1358-63.
- Wortelboer HM, van der Linden EC, de Kruif CA, Noordhoek J, Blaauboer BJ, van Bladeren PJ, Falke HE. Effects of indole-3-carbinol on biotransformation enzymes in the rat: in vivo changes in liver and small intestinal mucosa in comparison with primary hepatocyte cultures. Food Chem Toxicol. 1992 Jul;30(7):589-99.
- Parkin DR, Malejka-Giganti D. Differences in the hepatic P450-dependent metabolism of estrogen and tamoxifen in response to treatment of rats with 3,3’-diindolylmethane and its parent compound indole-3-carbinol. Cancer Detect Prev. 2004;28(1):72-9.
- Gao X, Petroff B, Oluola O, Georg G, Terranova P, Rozman K. Endocrine Disruption by Indole-3-carbinol and Tamoxifen: Blockage of Ovulation. Toxicol Appl Pharmacol. 2002 Sep 15;183(3):179
- Herrmann S, Seidelin M, Bisgaard HC, Vang O. Indolo[3,2-b]carbazole inhibits gap junctional intercellular communication in rat primary hepatocytes and acts as a potential tumor promoter Carcinogenesis. 2002 Nov;23(11):1861-8.
*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.