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Effect on Estrogen Metabolism

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Diindolylmethane


Diindolylmethane & Estrogen Balance

Diindolylmethane (DIM) is the most active cruciferous derived substance for promoting beneficial, estrogen metabolism in both women and men. DIM is formed from cruciferous vegetables including broccoli, cauliflower, cabbage and brussels sprouts.

DIM is actually formed in vivo (in the body) from its precursor indole, Indole-3-carbinol (I3C), after the enzymatic release of I3C from parent glucosinolates found in all cruciferous vegetables.

The supplemental use of DIM began with early experiments which demonstrated that animal diets with added diindolylmethane, like diets with added cruciferous vegetables, prevented chemically induced cancer.

Pure diindolylmethane was first used in 1987 as a dietary supplement in animals, shown to be non-toxic, and to prevent breast cancer caused by the well known human carcinogen, dimethybenz[a]anthracene. Similarly, the initiation pathway to chemically induced colon cancer was inhibited with the diindolylmethane precursor, I3C.

The mechanisms by which DIM prevents cancer in animals has subsequently been shown to involve a reduction in activity of the estrogen receptor system, promotion of beneficial estrogen metabolism, and support for selective apoptosis, or “programmed cell death” which removes damaged cells.

Supplemental use of DIM in humans is effective in adjusting the pathways of estrogen metabolism to favor the production of 2-hydroxyestrogen metabolites (see diagram below).

These shifts in estrogen metabolites were significant and showed an approximate 75% increase in production of 2-hydroxyestrone and a 50% decrease in 16-hydroxyestrone. An increased proportion of 2-hydroxy metabolites is correlated to protection from breast cancer.

This relationship has been documented in two prospective studies. Additional case-control studies have also documented that low levels of 2-hydroxy metabolites are associated with breast cancer in women, breast cancer in men, familial risk of breast cancer, uterine cancer, cervical cancer, and systemic lupus erythematosis.

An increase in the rate of breast cancer has now been associated with lupus.

Many established risk factors for breast cancer including obesity, high fat diets, and diets deficient in omega-3-fatty acids have also been correlated with low 2-hydroxy metabolite production.

Diindolylmethane is uniquely active with regard to its ability to favorably modify estrogen metabolism in the direction of greater 2-hydroxy estrogen production, whereas I3C is highly unstable, chemically reactive, and unpredictable.

It’s safe, long term use in dietary supplements is of questionable value. I3C has been shown to be a precursor dietary indole, without activity until converted to DIM in the acid environment of the stomach. This process can be inefficient, especially with diminished gastric acid production.

Therefore, in addition to lacking shelf life, I3C has little or no biological activity until it is converted to DIM.

In contrast to I3C, diindolylmethane is highly stable, requires no conversion in the stomach, and is the most active cruciferous indole in promoting beneficial estrogen metabolism.

Unlike soy isoflavones, genistein and daidzein, DIM is not an estrogen mimic or “phytoestrogen” and has no inherent estrogenic activity. DIM acts to balance the natural response to estrogen by adjusting the activity of metabolic cytochrome enzymes and specialised estrogen receptor molecules.

In dividing cells this limits the growth promoting signal from estrogens by reducing the level of activity of the estrogen receptor system. The compound 2-methoxyestrogen inhibits cell division by slowing the organisation of tubulin, the subcellular cytoskeleton necessary for division of chromosomes.

DIM enhances the protective mechanism of apoptosis, or programmed cell death, promoting beneficial elimination of damaged cells. The combination of these effects on cell behaviour, sets DIM apart from all other dietary substances and gives diindolylmethane a unique capability to promote beneficial actions of the estrogens.

Active apoptosis is central to preventing the initiation and promotion of breast, colon, and other cancers. Since these effects are specific to rapidly dividing cells, diindolylmethane does not prevent the beneficial effects of estrogen in supporting the health of the central nervous and skeletal systems.

In a nutshell, DIM creates a safer cellular environment for estrogen.



The Importance of Diindolylmethane Supplementation for Pre and Postmenopausal Women

In premenopausal women, the first age-related hormonal imbalance involves a decreased production of progesterone. This reduction in progesterone output during the second half or luteal phase of the menstrual cycle can cause irregular periods and contribute to premenstrual mood disorders.

The “good estrogen” metabolites, 2-hydroxy and 2-methoxy estrogen are notable in that they stimulate increased progesterone production from ovarian cells. By promoting this 2-hydroxy production, supplementation  with DIM can help support progesterone production and maintain progesterone levels throughout the perimenopause.

This balancing effect can benefit disorders associated with estrogen-progesterone imbalance including chronic, recurring breast pain, fibrocystic disease, and endometriosis.

The fearful nature of breast cancer makes hormonal replacement unacceptable to many post-menopausal women. Adding to this dilemma is the current wider availability of dehydroepiandrosterone (DHEA), a precursor adrenal steroid and the natural source of estrogen in post menopausal women.

DHEA has been shown in long term clinical studies to promote bone mineralization without uterine stimulation, and has demonstrated protection to breast tissue from cancer initiation and growth.

The importance of supplementation with diindolylmethane is that this approach can decrease estrogen-related breast cancer risk in the majority of women. This includes women taking estrogen, DHEA, phytoestrogen supplements, or no hormonal replacement at all.

The increased risk of breast cancer from postmenopausal estrogen administration can be eliminated by the complementary step of adding cruciferous based supplements like diindolylmethane.


The Importance of Healthy Estrogen Metabolism in Men’s Health

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.

Diindolylmethane and environmental estrogens, high fat diets and pesticide residues in food all serve as additional sources of ele-vated estrogen exposure (often referred to a xenoestrogens - "foreign estrogens"). In addition, high fat diets, especially those rich in animal fats or omega-6 fatty acids can shift the metabolic pathways of estrogen towards the 16-hydroxy metabolites.

These “bad estrogens” are associated with higher rates of benign breast disease, and cancer in both women and men.

A study of European women confirmed that dietary exposure to the estrogenic pesticide, Dieldrin (a now banned organochlorine that is an environmental contaminant), was associated with increased risk of subsequent breast cancer. Exposure of breast cells in culture to organochlorine pesticides like Dieldrin increases the production of 16-hydroxy estrogen metabolites.

Alternatively, diets rich in omega-3 fatty acids from fish or supplemented with diindolylmethane produce more of the “good estrogens” identified as the 2-hydroxy metabolites of estradiol and estrone. The use of cruciferous indoles in test animals has been shown to be associated with the prevention of spontaneous, estrogen related cancers of the breast and uterus.

When tested in animals, DIM is unique in its effectiveness to favorably shift estrogen metabolism and decrease the over activity of the estrogen receptor system. The supplemental use of DIM allows women to promote and maintain a safer metabolism of estrogen. Diindolylmethane also increases the safety of exposure to estrogen derived from DHEA.

This supports the rationale for long term supplementation with DHEA by both men and women. Documented, age related changes in men support their need for an improved metabolism of estrogen. Diindolylmethane use by men provides a promising dietary means to minimise the impact of increased estrogen on atherosclerosis and prostate disorders characteristic of andropause ("male menopause").

These important benefits for successful aging in men and women all relate to an optimal and safer “estrogen balance”.
 
Estrogen diagram  (112KB)
  
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