Background
Diindolylmethane (DIM) is a phytonutrient found in indole rich, cruciferous vegetables such as cabbage, brussel sprouts, cauliflower and broccoli. DIM is one of the most abundant and biologically active cruciferous indoles.[1]

Microencapsulated DIM is a specially designed DIM complex with proven clinical activity. This patented DIM complex features an enhanced bioavailability delivery system. As a supplement it does not need to be catalyzed within the digestive system to function effectively.

Accumulating evidence shows supplemental DIM assists the activity of the enzymes that maintain healthy estrogen hormone levels in both men and women and may be used to support female healthy hormone balance.[2],[3],[4],[5],[6]

Health and Estrogen Hormone Levels
Estrogens are a group of three biochemically distinct hormones, estradiol (E2), estrone (E1), and estriol (E3). E2 and E1 are considered the parent estrogens, whereas E3 is metabolized from 16-alpha hydroxestrone.[1],[5]

Estrogen is enzymatically converted to specific estrogen metabolites such as 16-alpha hydroxyestrone, 4-hydroxyoestrone, 4-methoxyoestrogens, 2-hydroxyoestrogens and 2-methyoxyoestrogens. A healthy ratio of these estrogen metabolites plays an important role in supporting hormonal health.[1],[5]

As a supplement microencapsulated DIM has a favorable influence on the healthy ratio of estrogen metabolites. Improved metabolism of available estrogen supports healthy expression of this key hormone. A number of the common symptoms attributed to estrogen excess may be due to over production of unfavorable estrogen metabolites.[1],[5]

Research shows supplemental DIM specifically assists activity of hepatic cytochrome P450 enzymes, CYP1A2 and to a lesser extent CYP1A1, necessary to promote greater 2-hydroxylation of estrogens.[1],[5][7] This effect is possible using DIM at physiologically achievable doses.3

Microencapsulated DIM supports favorable changes in estrogen metabolism toward 2-hydroxylation. The protective 2-hydroxyoestrogen and 2-methyoxyoestrogen metabolites are termed ‘favorable’ estrogen metabolites.[8] Whereas 4-hydroxyoestrone and 16-alpha-hydroxyoestrone are often termed ‘unfavorable’ estrogen metabolites when hyper driven.[5],[8]

The 2-hydroxyestrogen metabolites possess lower hormonal potency than estradiol, a relatively high clearance rate and O-methylation rate by catechol-O-methyltransferase (COMT). However, DIM should not significantly reduce circulating estradiol or estrone levels when appropriately prescribed.[9],[4]

Bioavailable DIM in a Clinical Setting
Microencapsulated DIM supports healthy estrogen activity. For this reason, the use of herbal extracts with phytoestrogenic activity may form an effective dual strategy to help maintain healthy hormone balance.

Microencapsulated DIM may assist hormone health when taken with Hormone Replacement Therapy (HRT) and the oral contraceptive pill (OCP). DIM has no action on CYP3A4, the enzyme that metabolizes the OCP, therefore, microencapsulated DIM does not affect efficacy of the OCP. Hormonal prescribers should be advised of concomitant DIM use.

Microencapsulated DIM may support hormone balance when taken with bioidentical hormone replacement therapy (BHRT). Microencapsulated DIM may assist effective metabolism of increased available estrogen.

DIM – Key benefits

Support Healthy Hormone Balance

Estrogen Metabolism
Estrogen receptors are present throughout the human body. Estrone (E1) and estradiol (E2) are potent estrogens, whereas estriol (E3) is considered a relatively weak estrogen. Estrogens are eliminated from the body by metabolic conversion to various metabolites that are excreted in the urine and/or feces.[10]

The first step in the metabolism of estrogens is via hydroxylation by CYP450 enzymes. Since most CYP450 enzymes are abundantly expressed in the liver, metabolism of estrogens mainly occurs here. Emerging evidence now demonstrates that the major physiological effects of estrogen are due to the hydroxylated metabolites that are formed from estradiol and estrone.[10]

The principal hydroxylation products from estradiol and estrone are 2-hydroxyoestrone, 4-hydroxyoestrone and 16-alpha hydroxyestrone. Individuals who metabolize estradiol and estrone to unbalanced ratios of 4-hydroxyoestrone and 16-alpha hydroxyestrone may be at increased risk of serious health issues. The 16-alpha hydroxyestrone metabolites retain potent hormonal activity and are associated with symptoms of estrogen excess. At the same time detrimental effects including reduced bone formation possibly initiated from low estrogen levels may occur if 16-alpha hydroxestrone metabolites are too low – balance is the key here.[11]

The concentration of 4-hydroxyoestrone metabolites is smaller, so the impact is considered less than the more abundant 16-alpha hydroxyestrone metabolites. However, the 4-hydroxyoestrone metabolites may be more potent as they are known to be long acting and have the ability to generate potentially mutagenic free radicals.[12]

The 4-hydroxyoestrone metabolites are specifically catalyzed via the CYP1B1 pathway, an enzyme which is highly expressed in the estrogen target tissues of the breasts, ovaries and uterus. 4-hydroxyoestrone production provides a measure of CYP1B1 activity.[13]

Apart from estrogen metabolism, CYP1B1 is also involved in the metabolic activation of some environmental carcinogens.[11] Research has indicated for many years that the abnormal elevation of 4-hydroxyoestrones may be linked in part to the activation of Arylhydrocarbon receptor (Ahr). This metabolic imbalance may increase the risk of serious estrogen related health issues.[14]

Microencapsulated DIM may act as an Ahr modulator and act against epigenetic activation of COX-2 expression by AhR agonists.12 The actions of toxic quinone metabolites produced by high levels of 4-hydroxyoestrone metabolites may have negative implications.[13],[14],[15] Since 4-hydroxyoestradiol generates free radicals from the reductive-oxidative cycling with the corresponding semiquinone and quinone forms, which cause cellular damage, the specific and local formation of 4-hydroxyestradiol may impact breast and endometrial health.[16],[17]

2-hydroxyoestrone and its metabolite 2-methoxyoestrone have opposite biological properties and are generally considered protective. In addition, cell proliferative activity of the 2-hyroxy metabolites is nil, while 16-alpha hydroxyestrone is a powerful estrogen agonist. Higher levels of 2-hydroxyoestrone metabolites are associated with improvements in hormone balance. Higher levels of the 2-hydroxyoestrone metabolites are associated with a reduction in symptoms associated with estrogen dominance.[18],[19],[20]

Optimal hormone balance is dependent on an ideal ratio of 2-hydroxyoestrone, 4-hydroxyoestrone and 16-alpha hydroxyestrone metabolites and then downstream conversion to 2-methoxyoestrogen and 4-methoxyoestrogen metabolites.[18],[19],[20] Adequate supply of nutrients that support methylation may assist the conversion of hydroxyestrogen to methoxyestrogen metabolites. Catechol-O-methyltransferase (COMT) catalyzes the methylation of catechol estrogens to methoxy estrogens.[21]

A small randomized double-blind crossover intervention study of pre-menopausal women with cyclical mastalgia was published in JANA in 2005. Symptoms were monitored daily in a ‘breast pain dairy’ with significant reductions in the duration, and severity of breast pain noted in microencapsulated DIM participants, but not the placebo group.[4]

Furthermore, microencapsulated DIM demonstrated a carryover effect. Three months after supplementation ceased an improved 2-hydroxyoestrone/16-alpha hydroxyestrone urinary ratio remained. Researchers proposed this was primarily due to an increase in the 2-hydroxyoestrone fraction.[4]

Microencapsulated DIM is highly indicated for the support of female healthy hormone balance.[5],[6],[17] Supplementation of bioavailable DIM can assist transformation of available estrogen to 2-hydroxyoestrone and 2-methoxyoestrone, which have less estrogenic effects. DIM therefore has the potential to greatly reduce estrogen exposure.[24],[25],[26],[27]

Above Figure. Relationship of serum estrogens and estrogen metabolites to postmenopausal breast cancer risk. Falk et al. Breast Cancer Research 2013, 15:R34:[22] Adapted from Fuhrman et al.[61]

Support for Prostate Health
Estrogen has a significant effect on prostate gland homeostasis.[28],[29] There is accumulating evidence that greater conversion of estrogen down the 2-hydroxylation metabolic pathway may support prostate health. Conversely, elevated 16-alpha hydroxylation and 4-hydroxylation are associated with increased dysfunction.[30],[31]

Reducing activity of both the androgen and estrogen receptors in the prostate supports the health of this endocrine organ. The biological activity of testosterone and dihydrotestosterone is thought to occur predominantly through binding to the androgen receptor.[32],[33] The estrogen receptor is also active in the prostate tissue and has shown to contribute to prostate enlargement.[34],[35] Microencapsulated DIM may promote prostate health.[36],[37],[38],[39],[40],[41],[42]

Monitoring Estrogen Metabolism
Estrogen metabolite testing detects the urinary products of estrogen metabolism. As the estrogen metabolites are modifiable by diet, lifestyle and nutritional changes, this type of testing is useful for establishing risk, and implementing preventative health strategies.[43]

Human use of absorbable DIM has been shown to promote a dose responsive upward effect on the urinary ratio 2-hydroxyoestrone/16-alpha hydroxyestrone metabolites, demonstrated by Enzyme-Linked ImmunoSorbet Assay (ELISA) testing of urine before and after use.[4],[16]

While attention in the past has focused on testing 2/16 hydroxyestrone ratios, substantial evidence suggests that an assessment of 4-hydroxyoestrone and the ratio of methoxyestrogens is also important.

4-hydroxyoestrone production provides a measure of CYP1B1 activity which metabolizes both estrogen, and environmental chemicals. Overactivity of this CYP 450 enzyme pathway is associated with serious health issues. CYP1B1 can activate environmental procarcinogens and catalyze the conversion of estrogens to genotoxic catechol estrogens.[44]

A few words about the ‘Estrobolome’
The Estrobolome is defined as ‘the aggregate of enteric bacterial genes capable of metabolizing estrogens’.[45],[46] Conjugated estrogens are excreted within the feces, urine and bile, however significant amounts of estrogen are reabsorbed. Certain bacteria, particularly those that contain hydrolytic enzymes, beta-glucuronidases and beta-glucosidases, possess activity in the gut that may lead to the deconjugation of estrogen and its reabsorption via enterohepatic circulation.[46]

Factors such as age, ethnicity, alcohol, certain drugs, antibiotics and diet may affect estrobolome composition. High fat and protein diets have been associated with increased fecal beta-glucuronidase activity, whereas high fiber diets have been associated with reduced activity.[46]

Adequate fiber intake supports regular elimination and may reduce 17-epiestriol concentrations. Fiber intakes over 25g/day are associated with increased 4-methoxyestradiol levels compared to intakes of less than 15g/day in premenopausal women.[46]

DIM the major active of I3C
DIM is the major in vivo condensation product formed after the enzymatic release of indole-3 carbinol (I3C) from glucosinolates found in all cruciferous vegetables.

Following ingestion, I3C is rapidly converted into several compounds.[47] DIM is the dominant metabolite formed from I3C, with research indicating that I3C may simply serve as a precursor to DIM.[10] A number of the biological activities of I3C may not be attributed to the parent compound but rather to DIM and other derivatives.[48],[49]

Notably, I3C is not stable in the low pH, digestive milieu with 84% conversion to a variety of DIM and non-DIM compounds in 24 hours.[50],[51] I3C, the natural precursor to DIM, is formed from a condensation reaction in which one I3C molecule combines with another releasing formaldehyde.[52]

The resulting DIM is a ‘di-indole’ or double molecule, formed from two I3C molecules. Exposure to a highly acidic gastric environment produces less DIM and a variety of other double and triple chemical species, while a less acidic gastric environment produces more DIM from I3C. The reaction is variable and unpredictable.[30],[53],[54] I3C not only converts to DIM, the major acid condensation product, it can also form varying amounts of non-DIM metabolites such as indolocarbazole (ICZ), linear trimer (LTR), cyclic trimer (CTR) and ascorbigen.[24],[55],[56],[57]

The exact mix of metabolites formed from I3C depends upon the acidity of the stomach. This unpredictable process is modulated by achlorhydria, and consumption of proton-pump inhibitors or antacids.[58]

The reaction products from I3C have a complex effect on estrogen metabolism and some activate the Aryl Hydrocarbon Receptor (AhR). The AhR is a cellular protein which interacts with a multitude of xenoestrogens.[57] The activated AhR induces the cell nucleus to produce more of the CYP1B1 enzyme, which produces 4-hydroxyoestrogen metabolites and other toxic metabolites from poly cyclic aromatic hydrocarbons.[56] Research suggest that DIM may act as an AhR modulator.[14]

Generic Diindolylmethane
In its pure crystalline state DIM is insoluble and therefore poorly absorbed. Greater bioavailability is achieved with an absorption-enhanced formulation.

Microencapsulated DIM utilizes solubility enhancing microencapsulation technology for effective absorption of DIM. This has been proven to significantly increase sustained gastrointestinal absorption of DIM.[6] Oral administration of Microencapsulated DIM, a patented formulation of DIM, exhibits approximately fifty percent higher bioavailability than an unformulated crystalline DIM.[59]

Highlights
Microencapsulated Diindolylmethane is a unique and highly absorbable diindolylmethane (DIM) as found in cruciferous sources with demonstrated clinical activity.[1],[30] Microencapsulated diindolylmethane assists the favorable metabolism of estrogen down the 2-hydroxylation pathway.[1],[5] This beneficial shift in metabolism can help support healthy hormone balance.[5],[24],[25]

Excipients
Cellulose microcrystalline, calcium hydrogen phosphate, silicon dioxide, and magnesium stearate (vegetable source).

Warnings
Microencapsulated Diindolylmethane is not recommended for use if you are pregnant, breastfeeding, or planning a pregnancy.

Precautions & Considerations

Harmless changes in urine color may occur with Microencapsulated Diindolylmethane.
Increased water consumption can reduce this side effect.
Symptoms of nausea and/or headaches may occur with Microencapsulated DIM.
Microencapsulated DIM assists activity of hepatic cytochrome P450 enzymes (CYP1A2) pathways. Nutrients required to support phase 2 liver detoxification pathways can assist in reducing these symptoms.
A short-term increase in symptoms with Microencapsulated DIM may be due to increased metabolism of available estrogen.
Microencapsulated DIM does not contain goitrogenic compounds which could affect thyroid function.
Microencapsulated DIM is not phytoestrogenic and has no inherent estrogenic activity. Bioavailable DIM can be used in used in conjunction with phytoestrogenic herbs.
Microencapsulated DIM may assist hormone health when taken with Hormone Replacement Therapy (HRT)
Microencapsulated DIM may assist hormone health when taken with the oral contraceptive pill (OCP). Microencapsulated DIM has no inducing action on CYP3A4, the enzyme that metabolizes the OCP. Therefore, Microencapsulated DIM does not affect efficacy of the OCP.
Microencapsulated DIM may assist effective metabolism of increased available estrogen when taken with bioidentical hormone replacement therapy (BHRT).
Combined use of Microencapsulated DIM and Tamoxifen is not recommended.[60]
Combined use of Microencapsulated DIM and Zoladex is supported.
Microencapsulated DIM should be used with caution in patients taking anticoagulation medications.
Individuals on prescribed medications that are metabolized down the CYP1A1/1A2 pathways should seek medical advice. Eg. Microencapsulated DIM may lead to a moderate increase in the drug Olanzapine. [61]

References

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What is DIM?