Indolplex^® contains the key ingredient DIM™ (diindolylmethane). DIM is naturally present in vegetables such as broccoli. One tablet of Indolplex^® is equivalent to approximately two pounds of broccoli. The role of DIM in the body is to support the healthy metabolism of estrogen, which is important for both men and women. Indolplex^® is a patented technology that enhances the absorption and bioavailability of DIM.

INTRODUCTION
The healthy effects of eating vegetables have been known for many years. It is only recently, however, that scientists have worked to determine which substances in these foods provide specific benefits. Diindolylmethane (DIM) is one of these substances. Because the size and shape of DIM is similar to natural hormones, this food substance, which works through the hormonal system, is a promoter of hormonal balance and overall metabolism.¹
Though discovered over ten years ago, the connection between plant-derived dietary ingredients and estrogen is just beginning to be appreciated. This connection may be helpful in explaining why people living in developed countries, but lacking dietary phytonutrients, suffer disproportionately from hormonal imbalance.² Research has shown that supplemental use of a single cruciferous phytonutrient can support the metabolism of estrogen.^3,4 This change in metabolism has the power to greatly reduce unhealthy estrogen exposure.

Diindolylmethane
Diindolylmethane (DIM), a dietary indole, is a naturally occurring component of Brassica (cruciferous) vegetables, such as cabbage, broccoli, Brussels sprouts, and cauliflower. DIM is formed from Indole-3 carbinol (I3C) after plant enzymes are released by crushing or chewing the vegetable. DIM is also formed directly from I3C, without enzymes, in an acidic environment such as in the stomach, when I3C is taken as a food supplement.^5,6

Hormones
Hormones are substances secreted by specialized cells that affect the metabolism or behavior of other cells possessing receptors for the hormone. Hormones are conveyed throughout the body by the blood. They exert a physiological control effect on other cells in the body. ^7-9 Hormones may be hydrophilic (water loving), like insulin, in which case the receptors are on the cell surface or lipophilic (lipid or fat loving), like the steroids, where the receptor can be intracellular. Some problems may be stimulated by hormones, while other problems may be inhibited by hormones.^7,8
Estrogen, progesterone, and testosterone are called sex hormones because they strongly affect the reproductive system. However, they also have many other functions in the body. For example, estrogen helps to maintain healthy bones and skin in both women and men. Likewise, testosterone is present in both men and women, and supports healthy bones and muscles. Testosterone can also improve energy, mood, and libido.¹⁰
Long term exposure to estrogens, in the form of hormone replacement therapy or xenoestrogens (estrogen mimics), is associated with several health risks.^11,12 The ratio of estrogen metabolites (e.g. 2-hydroxyestrone over 16-hydroxyestrone) is an established indicator of hormonal balance in women and men, influencing the health of the breast, endometrium, uterus, cervix, prostate and other tissues.^13-22 Effective estrogen clearance is a growing concern among health care providers, and its implications for gynecologic health and healthy cell development are significant:

• The normal aging process is characterized by increased activity of aromatase enzymes that convert DHEA and testosterone metabolites into estrogen.¹⁴ Modulation of this phenomenon can reduce age-related exposure to excessive estrogen and promote a more favorable balance of estrogen metabolites.
• Exposure to exogenous estrogens and estrogen-mimics (xenoestrogens) can cause hormonal overstimulation, leading to imbalances in estrogen metabolites. This may affect the female and male reproductive systems.⁵
• Imbalances of estrogen metabolites can lead to a reduction in the efficiency of protective apoptosis (programmed cell death) in various tissues.⁵

Induction and modulation of enzymes regulating hepatic (liver) Phase I and Phase II detoxification enhances the metabolism required for the elimination of various toxic xenobiotics (a chemical substance not produced by the body, and thus foreign to it),^23,24 and restoration of estrogen balance.

HOW DOES IT WORK?
Cruciferous vegetables contain several phytochemicals capable of significantly modifying the metabolism of estrogens. These include indole-3-carbinol (I3C), phenethyl isothiocyanate (PEITC), sulforaphane and diindolylmethane (DIM). All four of these phytochemicals arise from the hydrolysis of glucosinolates, a group of parent compounds that are found in Brassica family vegetables and are responsible for their distinctive flavor. In the body, I3C is converted into DIM, its bioactive form. Despite being rich sources of DIM, it is difficult to consume cruciferous vegetables in sufficient quantities to consistently affect estrogen metabolism or support detoxification enzymes.⁵
In one study, consumption of 500 grams per day of broccoli produced only a minor shift in estrogen metabolism.²⁵ Consumption of larger quantities would be necessary to obtain a desirable level of glucosinolates, and this is problematic because of gastrointestinal side effects.²⁶
I3C and DIM modify cytochrome p450 (CYP) enzyme activity and support detoxification.
The current drug-nutrient interactions that have been described for St. John's Wort and grapefruit juice do not apply to Indolplex.^® St. John's Wort causes an increase in the metabolism of various drugs by induction of CYP3A enzymes. Grapefruit juice is an inhibitor of this enzyme system, but does help in the absorption of DIM because these enzymes (CYP3A) are involved in DIM absorption. DIM enhances the activity of the CYP1A enzymes. These are the enzymes that are important in healthy estrogen metabolism.²⁷
Both I3C and DIM have been shown to increase the production of 2-hydroxyestrogen metabolism.⁵ DIM is the most potent inducer of 2-hydroxylase, the enzyme responsible for this beneficial shift in estrogen metabolites.²⁸ DIM induces 2-hydroxyestrone (2OH1) and 2-hydroxyestradiol (2-OH2) in diverse tissues, leading to net inhibition of excessive estrogen stimulation. Once present in the circulation, 2-0H1 and 2-0H2 are metabolized by catechol-O-methyl transferase (COMT), resulting in 2-methoxyestrone and 2-methoxyestradiol. These critical metabolites have been shown to promote healthy cell development in animals and humans.^6,29-41
DIM is the most active and important of the dietary indoles, at least 10 times more potent than its precursor, I3C. DIM is also more beneficial than 13C as a dietary supplement, because I3C may promote CYP metabolism to reactive intermediates. I3C is unstable, reacts unpredictably during storage and digestion, and lacks biologic activity unless converted by the body into DIM.¹⁰
Diindolylmethane is extremely insoluble in both water and lipids, and poorly absorbed without a biodelivery vehicle. Indolplex^® provides an effective delivery system that has undergone testing in animal and clinical settings. Bioavailability testing in animals established at least a tenfold advantage of Indolplex^® over unprocessed DIM.⁴² In clinical testing, supplementation of volunteers with pure, unprocessed DIM did not alter the metabolite ratio. However, repeat testing of the same volunteers at much lower doses using Indolplex^® did beneficially alter the metabolite ratio, favoring an increase of 2-hydroxy over 16-hydroxy estrogen metabolites, promoting metabolism to the desirable 2-methoxy estrogen metabolites.⁴³
Indolplex^® is the first dietary supplement with research that associates changes in estrogen metabolites with indices of health. Indolplex^® supplies a beneficial quantity of DIM to supplement cruciferous vegetables in the diet. Use of DIM in animal studies at hundreds of times the dose provided by Indolplex^® produced no adverse effects.⁴⁴
DIM is less reactive and less of an enzyme inducer than I3C. Doubling the typical dose of I3C from 400 to 800 mg/day can cause unwanted side effects in humans.⁴⁰ No side effects of any sort are seen with DIM even when the typical dose of 150mg/day is tripled to 450 mg/ day.⁴⁵

RECOMMENDATIONS
Take 2 tablets daily with food. If less support is needed, take 1 tablet daily with food.

PRECAUTIONS
Do not use if pregnant or nursing. This precaution is included because pregnancy is a time of high fetal sensitivity to environmental and nutritional substances, and currently there are no human studies to support the safety of Indolplex^® use during pregnancy or nursing. However, no prenatal or nursing adverse effects have yet been identified.
Harmless changes in urine color may occur with the use of this product. This color change reflects the presence of metabolites of DIM that have an amber color. Such colored metabolites are seen with all indole substances. These changes are also seen with the consumption of large amounts of DIM-containing cruciferous vegetables. Increasing water intake to 6-8 glasses per day can reverse the color change. There has been no change in urine odor noted.