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  Diindolylmethane DIM / Indole 3 Carbinol IC3  
 
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The stronger form of estrogen (estradiol) can be converted into the weaker form (estriol) without using drugs. Estriol is considered to be a more desirable form of estrogen; it is less active than estradiol, so when it occupies the estrogen receptor it effectively blocks estradiol's strong "grow" signals.

Using a natural substance, such as Diindolylmethane - a stable indole found in cruciferous vegetables - researchers were able to increase the conversion of estradiol to estriol by 50% in 12 healthy people. Next, they tested the natural substance in female mice prone to developing breast cancer. The incidence of cancer and the number of tumors fell significantly. This substance was Indole-3-carbinol (IC3) or DIM (diindolylmethane), phytochemicals isolated from cruciferous vegetables (broccoli, cauliflower, Brussels sprouts, turnips, kale, green cabbage and mustard seed). Additionally, the level of an estrogen metabolite associated with breast and endometrial cancer (16-alpha-hydroxyestrone) fell.

In 1997, researchers at Strang Cancer Research Laboratory at Rockefeller University discovered that when DIM (diindolylmethane) changes "strong" estrogen to "weak" estrogen, it stops human cancer cells from growing and provokes the cells to self-destruct (apoptosis). Subsequent studies done at the University of California at Berkeley show that DIM (diindolylmethane) inhibits some human breast cancer cells from growing by as much as 90% in culture. Growth arrest does not depend on estrogen receptors.

16-alpha-hydroxyestrone (16OHE) and 2-hydroxyestrone (2OHE) are metabolites of estrogens. 2OHE is biologically inactive, while 16OHE is biologically active meaning that, like estradiol, it can send those "grow" signals. In cases of breast cancer, the bad 16OHE is often elevated and the good 2OHE is decreased. Interestingly, cancer-causing chemicals change the metabolism of estrogen so that 16OHE is elevated. Studies show that people who take DIM not only have beneficial increases in estriol, they also have beneficial increases in 2OHE.

Low levels of the 2OHE have been linked to breast cancer (in both women and men), uterine cancer, cervical cancer and lupus. An immune disorder that affects mostly women, lupus appears related to estrogen metabolism.

Diindolylmethane is generally much more effective than I3C and less expensive. In the mid-1990s it was determined that IC3 was biologically inactive until converted to DIM (diindolylmethane), which in humans occurs in the digestive tract. I3C is converted into DIM through a process involving gastric hydrochloric acid (HCL). If a person is deficient in HCL, as commonly occurs in the elderly, I3C won't effectively convert into DIM. In contrast to I3C, diindolylmethane is highly stable, doesn't need any conversion in stomach acid, and is by far the most active phytochemical in promoting the synthesis of protective 2OHE. However, DIM is poorly absorbed unless "absorption enhanced" in some way. Please look for such wording on any DIM product you consider purchasing. It is generally agreed that 300mg of IC3 converts to 30-40mg of DIM (diindolylmethane).

As little as 0.5- 2mg mg/kg body weight/day of DIM has been demonstrated as an effective dose. The usual dosage of diindolylmethane for women is 100 - 200mg per day taken with food. When used for weight loss, the dosage used has been up to 400mg per day. It is used in association with carbohydrate restriction and exercise. The usual dosage of DIM for men is 200 - 400 mg per day taken with food. For men involved in a plan of muscular development and/or fat loss, the dose of DIM could be increased to 400 - 500mg per day.

More importantly from an anabolic point of view, the level of free testosterone rises in the blood with use of diindolylmethane. The mechanism behind this is that 2-hydroxy estrogens have a greater binding affinity for the blood proteins that "lock up" testosterone in the blood. Thus, these plasma binding proteins instead latch on to 2-hydroxy, leaving greater levels of free testosterone, including that produced through the use of supplemental prohormones.

The 2-hydroxy estrogens promoted by usage also increase testosterone synthesis through another mechanism. Estrogen, even more than testosterone itself, incurs a negative hormonal feedback loop to the pituitary gland, where the rate-limiting gonadotropin for testosterone synthesis, luteinizing hormone (LH) is synthesized and released. What this means is that high blood levels of estrogen, as may occur through aromatization of free testosterone, turn off the release of LH from the pituitary gland. This leads to a vicious biochemical cycle characterized by an imbalance between testosterone and estrogen in favor of the latter. These events, however, are nullified by 2-hydroxy, which doesn't provide the negative feedback message to the pituitary induced by estrogen. The net effect is greater testosterone synthesis in the Leydig cells of the testes, as well as lower levels of bad estrogen and all the effects that go with it.
 

 
 

Diindolylmethane DIM / Indole 3 Carbinol IC3 can help with the following:
 
 
Autoimmune  Lupus, SLE (Systemic Lupus Erythromatosis) / Risk
 There is an acceleration of the testosterone to estradiol conversion by an increase in aromatase activity in healthy SLE patients when compared to controls. Interestingly, "among SLE patients the aromatase activity varied inversely with the disease activity. Patients with SLE had decreased androgen and increased estrogen levels. Aromatase activity in SLE patients had significant direct correlation with estrogen levels. These data suggest that abnormal regulation of aromatase activity may partially explain the abnormalities of estrogen synthesis in SLE." These patients are relatively testosterone deficient. [Lupus 1992;1(3): pp.191-5] Aromatase blockers like DIM (diindolylmethane) and Chrysin can be considered. Diindolylmethane (DIM) is a stable indole found in cruciferous vegetables

Hormones

  Low Progesterone or Estrogen Dominance
 DIM (diindolylmethane) encourages the conversion of estrogens to safer forms and helps reduce elevated levels.

  Elevated Insulin Levels
 Diindolylmethane (DIM), a stable indole, has been reported to enhance insulin sensitivity and encourage abdominal fat loss.


Not recommended for:
  Low Testosterone Level
 The bulk of evidence indicates that DIM and IC3, though similar, can have differing effects on free testosterone and estrogen levels. Overall, these items may have the opposite effect of what is desired - increased free testosterone and reduced estrogens.

One contributor concluded:

I have not found any research to support DIM inhibiting Aromatase activity, in fact in may increase Aromatase activity. There is research to support that DIM increases conversion of some estrogen hormones into their estrogen metabolites. This reduction in estrogen hormones down regulates testosterone conversion to DHT, and DHT is an inhibitor of aromatase activity therefore aromatase activity increases. It is important to understand that estrogen also plays a role in total testosterone levels as increased levels of estrogen increases SHBG which binds free testosterone. Also decreased levels of estrogen increases LH and FSH which increases testosterone production and should result in higher free testosterone, but this will not result in higher total levels of testosterone due to decreased SHBG. Also keep in mind that if testosterone production is turned on high, the body may not produce enough DHEA to meet this new found demand.


Taking DIM should result in:
Lower Total Testosterone
Higher LH and FSH
Higher Free Testosterone (Unless Aromatase activity is to high, and is also subject sufficient DHEA production)
Lower DHT
Lower Estrone
Lower Estradiol
Higher Estriol


Clinical studies using testosterone injections, creams, or patches have often failed to provide a long-lasting, libido-enhancing effect in aging men. This is because testosterone can be converted to estrogen. The estrogen is then taken up by testosterone receptor sites in cells throughout the body. When an estrogen molecule occupies a testosterone receptor site on a cell membrane, it blocks the ability of serum testosterone to induce a healthy hormonal signal. It does not matter how much serum free testosterone is available if excess estrogen is competing for the same cellular receptor sites.

  Elevated Testosterone Level, Female
 Aromatase inhibitors like DIM (diindolylmethane), Indole 3 carbinol, and chrysin should be avoided, as they will enhance any preexisting androgen / estrogen dominance.

  Elevated Testosterone Level, Male
 Aromatase inhibitors like diindolylmethane (DIM), Indole 3 carbinol, and chrysin should be avoided, as they will enhance any preexisting androgen / estrogen dominance.

  Low SHBG
 Aromatase inhibitors like DIM (diindolylmethane), Indole 3 carbinol, and chrysin should be avoided, as they will enhance any preexisting androgen / estrogen dominance.

Risks

  Increased Risk of Breast Cancer
 Phytochemicals such as indole-3-carbinol (I3C) and sulforaphane are components of cruciferous vegetables which exhibit antitumorigenic activity associated with altered carcinogen metabolism and detoxification. Diindolylmethane (DIM) is a major metabolite of I3C formed in the gut and represents a new class of antiestrogens that inhibit breast cancer growth. It also encourages cells that are abnormally multiplying to stop reproducing and die.

We all know that eating fruits, vegetables and soy products provides essential nutrition for a healthy lifestyle, while obesity leads to the opposite. Yet proving the effect of nutrition, or obesity, on cancer is an experimental challenge and a focus for scientists. According to emerging evidence being presented at the 2007 Annual Meeting of the American Association for Cancer Research, eating well might still be one of the more pleasurable ways to prevent cancer and promote good health.

Eating such foods as broccoli and soy are believed to offer some protection against cancer, but how this occurs is not well-understood. Now, in laboratory experiments, researchers at the University of California, Los Angeles, have discovered a biological mechanism whereby two compounds in these foods might lower the invasive and metastatic potential of breast and ovarian cancer cells.

They found that diindolylmethane (DIM), a compound resulting from digestion of cruciferous vegetables, and genistein, a major isoflavone in soy, reduce production of two proteins whose chemotactic attraction to each other is necessary for the spread of breast and ovarian cancers.

When applying purified versions of DIM and genistein to motile cancer cells, the researchers could literally watch these cells come to a near halt. When either compound was applied, migration and invasion were substantially reduced.

"We think these compounds might slow or prevent the metastasis of breast and ovarian cancer, which would greatly increase the effectiveness of current treatments," said Erin Hsu, a graduate student in molecular toxicology. "But we need to test that notion in animals before we can be more definitive."

Both DIM and genistein are already being developed for use as a preventive and a chemotherapy treatment for breast cancer, although more extensive toxicological studies are necessary, the researchers say.

  Increased Risk of Ovarian Cancer
 We all know that eating fruits, vegetables and soy products provides essential nutrition for a healthy lifestyle, while obesity leads to the opposite. Yet proving the effect of nutrition, or obesity, on cancer is an experimental challenge and a focus for scientists. According to emerging evidence being presented at the 2007 Annual Meeting of the American Association for Cancer Research, eating well might still be one of the more pleasurable ways to prevent cancer and promote good health.

Eating such foods as broccoli and soy are believed to offer some protection against cancer, but how this occurs is not well-understood. Now, in laboratory experiments, researchers at the University of California, Los Angeles, have discovered a biological mechanism whereby two compounds in these foods might lower the invasive and metastatic potential of breast and ovarian cancer cells.

They found that diindolylmethane (DIM), a compound resulting from digestion of cruciferous vegetables, and genistein, a major isoflavone in soy, reduce production of two proteins whose chemotactic attraction to each other is necessary for the spread of breast and ovarian cancers.

When applying purified versions of DIM (diindolylmethane) and genistein to motile cancer cells, the researchers could literally watch these cells come to a near halt. When either compound was applied, migration and invasion were substantially reduced.

"We think these compounds might slow or prevent the metastasis of breast and ovarian cancer, which would greatly increase the effectiveness of current treatments," said Erin Hsu, a graduate student in molecular toxicology. "But we need to test that notion in animals before we can be more definitive."

Both diindolylmethane and genistein are already being developed for use as a preventive and a chemotherapy treatment for breast cancer, although more extensive toxicological studies are necessary, the researchers say.

  Increased Risk of Prostate Cancer
 Diindolylmethane may reduce prostate cancer incidence as it has been shown to stop human cancer cells from growing by (54-61%) and provoking the cells to self-destruct (apoptosis). DIM (diindolylmethane) also improves prostate function.

In two papers published in the Journal of Biological Chemistry (Mar 27, 2003) researchers report that DIM significantly halted proliferation of androgen-dependent human prostate cancer cells. In one of the studies, androgen-dependent prostate cancer cells treated with DIM (diindolylmethane) grew 70% less than androgen-dependent untreated cells. DIM also inhibited dihydrotestosterone (DHT) stimulation of DNA synthesis in the androgen-dependent cancer cells. These effects were not seen in androgen-independent prostate cancer cells.

To determine whether men are at risk for prostate cancer, they are usually tested for levels of prostate-specific antigen (PSA), a growth factor for prostate cancer. In prostate cancer cells, diindolylmethane reduced intracellular and secreted PSA protein levels caused by DHT. The researchers determined that DIMís molecular structure is similar to Casodex, a synthetic anti-androgen drug.

Tumors, Malignant

  Breast Cancer
 We all know that eating fruits, vegetables and soy products provides essential nutrition for a healthy lifestyle, while obesity leads to the opposite. Yet proving the effect of nutrition, or obesity, on cancer is an experimental challenge and a focus for scientists. According to emerging evidence being presented at the 2007 Annual Meeting of the American Association for Cancer Research, eating well might still be one of the more pleasurable ways to prevent cancer and promote good health.

Eating such foods as broccoli and soy are believed to offer some protection against cancer, but how this occurs is not well-understood. Now, in laboratory experiments, researchers at the University of California, Los Angeles, have discovered a biological mechanism whereby two compounds in these foods might lower the invasive and metastatic potential of breast and ovarian cancer cells.

They found that diindolylmethane (DIM), a stable indole, which results from digestion of cruciferous vegetables, and genistein, a major isoflavone in soy, reduce production of two proteins whose chemotactic attraction to each other is necessary for the spread of breast and ovarian cancers.

When applying purified versions of DIM (diindolylmethane) and genistein to motile cancer cells, the researchers could literally watch these cells come to a near halt. When either compound was applied, migration and invasion were substantially reduced.

"We think these compounds might slow or prevent the metastasis of breast and ovarian cancer, which would greatly increase the effectiveness of current treatments," said Erin Hsu, a graduate student in molecular toxicology. "But we need to test that notion in animals before we can be more definitive."

Both DIM and genistein are already being developed for use as a preventive and a chemotherapy treatment for breast cancer, although more extensive toxicological studies are necessary, the researchers say.

  Prostate Cancer
 Researchers at the University of California, Berkeley, have found that a chemical produced when digesting such greens as broccoli and kale can stifle the growth of human prostate cancer cells.

The findings show that 3,3'-diindolylmethane (DIM or just diindolylmethane), which is obtained by eating cruciferous vegetables in the Brassica genus, acts as a powerful anti-androgen that inhibits the proliferation of human prostate cancer cells in culture tests. Research shows that a chemical derived from cruciferous vegetables like broccoli could be effective against the growth of prostate cancer cells.

"As far as we know, this is the first plant-derived chemical discovered that acts as an anti-androgen," said Leonard Bjeldanes, professor and chair of nutritional sciences and toxicology at UC Berkeley's College of Natural Resources and principal investigator of the study. "This is of considerable interest in the development of therapeutics and preventive agents for prostate cancer."

Vegetables such as broccoli, Brussels sprouts, kale and cauliflower are rich sources of indole-3-carbinol (I3C), which the body converts into DIM during digestion. Over the years, Bjeldanes has been researching the anti-cancer properties of dietary indoles with co-author Gary Firestone, UC Berkeley professor of molecular and cell biology. [Journal of Biological Chemistry June 6, 2003 ]

In two papers published in the Journal of Biological Chemistry (Mar 27, 2003) researchers report that DIM (diindolylmethane) significantly halted proliferation of androgen-dependent human prostate cancer cells. In one of the studies, androgen-dependent prostate cancer cells treated with DIM grew 70% less than androgen-dependent untreated cells. DIM also inhibited dihydrotestosterone (DHT) stimulation of DNA synthesis in the androgen-dependent cancer cells. These effects were not seen in androgen-independent prostate cancer cells.

To determine whether men are at risk for prostate cancer, they are usually tested for levels of prostate-specific antigen (PSA), a growth factor for prostate cancer. In prostate cancer cells, DIM (diindolylmethane) reduced intracellular and secreted PSA protein levels caused by DHT. The researchers determined that DIMís molecular structure is similar to Casodex, a synthetic anti-androgen drug.

Uro-Genital

  Andropause/Male Menopause
 In men, there is a new appreciation of the effects of changing estrogen metabolism with aging, now identified as andropause. Diindolylmethane (DIM) is a stable indole found in cruciferous vegetables, and is a compound of interest for both men and women. German researchers have clearly documented a dramatic, aging-related accumulation of estrogen in human prostate glands. This work correlated age, estrogen accumulation, and the presence of benign prostatic hypertrophy. This underscores the role of estrogen as a growth promoting hormone in men as well as women. Tissue accumulation of estrogen is a unique hallmark of andropause, distinct from estrogen deficiency which characterizes menopause. Recent work shows that estradiol, the active form of estrogen, provokes increases in prostate specific antigen (PSA) production in human prostate tissue. This increase in PSA is as great as that seen with testosterone. Increased PSA production was specifically inhibited by 2-methoxyestradiol, the beneficial estrogen metabolite whose production is promoted by DIM.

Accumulation of estrogen during andropause is amplified by obesity since fat tissue is the site of conversion of both testosterone and DHEA into estrogen. In case control studies, higher levels of circulating estrogen predict the degree of prostate enlargement. More importantly, increased estrogen levels have been repeatedly noted as a risk factor for early atherosclerosis and heart attack. The risks of elevated estrogen in men further correlate to decreased ability to dissolve blood clots. The specific deficiency in men of an active, beneficial metabolism of estrogen leading to 2-methoxy estrogens would explain many, if not all, of these observations.

In studies culturing human vascular endothelial cells (HUVEC), it has been shown that 2-methoxy estradiol is a primary regulator of cell growth and apoptosis. Active and regulated apoptosis may contribute to the prevention of atherosclerotic plaque formation. At the basic level of lipoprotein status, 2-hydroxy and 2-methoxy estrogens are powerful antioxidants. In recent experiments, these metabolites, whose production is promoted by DIM (diindolylmethane), have been shown to prevent the oxidation of human lipoproteins. Lipoprotein oxidation is now accepted as an early, initiating event in atherosclerosis Ö While it remains to be demonstrated through intervention studies that diindolylmethane supplementation can slow the progression of prostate disease and atherosclerosis, it is clear that DIM supplementation in men can beneficially shift estrogen metabolism. - Michael A. Zeligs, M.D.
 
 


KEY
May do some good
Likely to help
Highly recommended
May have adverse consequences
Reasonably likely to cause problems







GLOSSARY

Anabolic:  Anabolic compounds: Allow the conversion of nutritive material into complex living matter in the constructive metabolism.

Apoptosis:  Programmed cell death as signaled by the nuclei in normally functioning human and animal cells when age or state of cell health and condition dictates. Cancerous cells, however, are unable to experience the normal cell transduction or apoptosis-driven natural cell death process.

Cancer:  Refers to the various types of malignant neoplasms that contain cells growing out of control and invading adjacent tissues, which may metastasize to distant tissues.

Carbohydrates:  The sugars and starches in food. Sugars are called simple carbohydrates and found in such foods as fruit and table sugar. Complex carbohydrates are composed of large numbers of sugar molecules joined together, and are found in grains, legumes, and vegetables like potatoes, squash, and corn.

Estrogen:  One of the female sex hormones produced by the ovaries.

Hydrochloric Acid:  (HCl): An inorganic acidic compound, excreted by the stomach, that aids in digestion.

Kilogram:  1000 grams, 2.2lbs.

Luteinizing Hormone:  Anterior pituitary hormone stimulating estrogen production by the ovary; promoting formation of progesterone by the corpus luteum in women and stimulating testosterone release in men.

Metabolism:  The chemical processes of living cells in which energy is produced in order to replace and repair tissues and maintain a healthy body. Responsible for the production of energy, biosynthesis of important substances, and degradation of various compounds.

Metabolite:  Any product (foodstuff, intermediate, waste product) of metabolism.

Milligram:  (mg): 1/1,000 of a gram by weight.

Phytochemicals:  Substances that occur naturally in plants and have been shown in research to possibly prevent or cure disease.

Pituitary:  The pituitary gland is small and bean-shaped, located below the brain in the skull base very near the hypothalamus. Weighing less than one gram, the pituitary gland is often called the "master gland" since it controls the secretion of hormones by other endocrine glands.

Protein:  Compounds composed of hydrogen, oxygen, and nitrogen present in the body and in foods that form complex combinations of amino acids. Protein is essential for life and is used for growth and repair. Foods that supply the body with protein include animal products, grains, legumes, and vegetables. Proteins from animal sources contain the essential amino acids. Proteins are changed to amino acids in the body.

Stomach:  A hollow, muscular, J-shaped pouch located in the upper part of the abdomen to the left of the midline. The upper end (fundus) is large and dome-shaped; the area just below the fundus is called the body of the stomach. The fundus and the body are often referred to as the cardiac portion of the stomach. The lower (pyloric) portion curves downward and to the right and includes the antrum and the pylorus. The function of the stomach is to begin digestion by physically breaking down food received from the esophagus. The tissues of the stomach wall are composed of three types of muscle fibers: circular, longitudinal and oblique. These fibers create structural elasticity and contractibility, both of which are needed for digestion. The stomach mucosa contains cells which secrete hydrochloric acid and this in turn activates the other gastric enzymes pepsin and rennin. To protect itself from being destroyed by its own enzymes, the stomachís mucous lining must constantly regenerate itself.

Testosterone:  The principal male sex hormone that induces and maintains the changes that take place in males at puberty. In men, the testicles continue to produce testosterone throughout life, though there is some decline with age. A naturally occurring androgenic hormone.