Safer Estrogen with Phytonutrition
This discovery proved that the metabolism and growth promoting activity of estrogen is modified by the intake of milligram amounts of dietary indoles from crucifers. When these cruciferous phytochemicals are added to the diet, estrogen action is regulated and its metabolism is shifted. This produces a predominance of 2-hydroxy and 2-methoxyestrogens. 4 These active metabolites have been called "good estrogens" 5, function as antioxidants 6, and have the power to eliminate damaged or cancerous cells throughout the body 7. Without these phytochemicals in the diet, there is increased production of a different, undesirable group of estrogen metabolites. These so-called "bad estrogens" act negatively to allow oxidation, to damage DNA, and to promote cancer 8.
A diet-derived imbalance in estrogen metabolism explains epidemiology showing a high prevalence of estrogen related disease, especially breast cancer, in societies consuming a diet low in total vegetable content.9 Supplemental use of diindolylmethane (DIM), the most active cruciferous indole, can restore and maintain a favorable balance of estrogen metabolites. Supplementation with DIM provides an innovative approach to reducing the estrogen-related risk of breast cancer. Therefore, DIM supplementation can increase the safety of estrogen replacement therapy in post menopausal women. In addition, aging-related alteration in estrogen metabolism is an under appreciated factor in men's health. DIM use by men promotes the same beneficial estrogen metabolism as seen in women. Improving estrogen balance in men may serve as a basis for enhancing prostate health.10
Supplemental use of DIM in humans is effective in adjusting the pathways of estrogen metabolism to favor the production of 2-hydroxy estrogen metabolites.4 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 (See Figure 1.). An increased proportion of 2-hydroxy metabolites is correlated to protection from breast cancer. This relationship has been documented in several case-control studies. 20,21,22 Case-control studies have also documented that low levels of 2-hydroxy metabolites are associated with breast cancer in women 23, breast cancer in men 24, familial risk of breast cancer 25, uterine cancer 26, cervical cancer 27, and systemic lupus erythematosis 28. An increase in the rate of breast cancer has now been associated with lupus 29. 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 estrone production.30 DIM is unique among all phytonutritionals with regard to its ability to favorably modify estrogen metabolism in the direction of greater 2-hydroxy estrogen production.
Extensive epidemiology has shown that consumption of crucifers in the human diet consistently reduces the occurrence of various cancers.31 With generous cruciferous intake the human diet provides up to 0.3 mg/kg of DIM. A recent human study was able to show that a daily intake of 500 grams of broccoli by volunteers slightly shifted the ratio of urinary estrogen metabolites, increasing urinary 2-hydroxyestrones in some of the subjects.32 Safe supplemental use of I3C was demonstrated in humans in 1992 33 , and confirmed in 199736. However, since I3C is highly unstable, its 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 is inefficient, especially in the elderly, with diminished gastric acid production. Therefore, in addition to lacking shelf life, I3C has no biologic activity until converted to DIM. In contrast to I3C, DIM is highly stable, requires no conversion in the stomach, and is the most active cruciferous indole in promoting beneficial estrogen metabolism.34
Though stable, the extreme water insolubility of DIM in its pure crystalline form requires an absorption enhancing delivery system for use in dietary supplements. "IndolplexTM" is such a formulation containing microparticles of DIM associated with a soluble matrix which improves absorption. IndolplexTM demonstrates predictable and enhanced absorption of DIM in dietary supplements.35 IndolplexTM, containing standardized DIM, provides the phytochemical in a consistent, absorbable form which mimics the intake of DIM from the diet. These amounts of DIM relate to that found in large portions of Brussels sprouts or broccoli but exceed amounts conveniently reached from diet alone.35
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 specialized estrogen receptor molecules. In dividing cells this limits the growth promoting signal from estrogen by reducing the level of activity of the estrogen receptor system. In a complementary way, DIM also promotes the pathways of metabolism of estrogen within cells to favor the cancer preventive metabolites, 2-hydroxy and 2-methoxy estrogen.7,39 These metabolites further limit cell division and growth through influence on the cell cycle which determines growth and replication. 2-methoxy estrogen inhibits cell division by slowing the organization of tubulin, the subcellular cytoskeleton necessary for division of chromosomes.40 DIM's support for the protective mechanism of apoptosis, or programmed cell death, promotes beneficial elimination of damaged cells.41 The combination of these effects on cell behavior sets DIM apart from all other dietary substances and gives DIM a unique capability to promote beneficial actions of estrogen. Active apoptosis is central to preventing the initiation and promotion of breast, colon, and other cancers.42 Since these effects are specific to rapidly dividing cells, DIM does not prevent the beneficial effects of estrogen in supporting the health of the central nervous and skeletal systems. In essence, DIM creates a safer cellular environment for estrogen.
In postmenopausal women, only about 20-30% of eligible women participate in long term use of supplemental estrogen. 43 This occurs despite compelling evidence as to the benefits of estrogen replacement, and relates to studies showing increased risk for breast and uterine cancer associated with prolonged HRT. 44 Even though this increase in risk is slight, the fearful nature of breast cancer makes hormonal replacement unacceptable to many women.45 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.46 DHEA, sold as an over the counter dietary supplement in the USA, has been shown in long term clinical studies to promote bone mineralization without uterine stimulation47, and has demonstrated protection to breast tissue from cancer initiation and growth48. The importance of supplementation with DIM 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.
DIM supplementation reduces undesirable metabolites of estrogen now known to be responsible for the cancer initiating and cancer promoting effects of estrogen.8 Supplemental DIM acts positively to support the pathways of estrogen metabolism which produce desirable metabolites associated with lower risk status for breast cancer and other estrogen-related disorders. The increased risk of breast cancer from postmenopausal estrogen administration can be eliminated by the complementary steps of adding cruciferous based supplements like DIM and reducing alcohol consumption to below 5 grams daily (equivalent to about 3 ounces of wine).49 The action of alcohol predictably raises circulating levels of estrogen from all sources by as much as 200% by interfering with its metabolism.50 If coupled with an unfavorable pathway of estrogen metabolism away from 2-hydroxy metabolites, alcohol can promote cancer whether or not supplemental estrogen is used. DIM supplementation is an effective and established means to assure a favorable pathway for estrogen metabolism. With its estrogen balancing effects, DIM provides a margin of safety and acts to reduce the negative consequences of estrogen elevation associated with moderate alcohol use.
Recent research clearly supports the benefits of maintaining
estrogen levels in women as natural production declines with
age. Post menopausal replacement of estrogen either through HRT
or derived from DHEA is associated with a list of confirmed benefits.51 In addition to a
decrease in overall mortality 52,
estrogen replacement confers better memory and a lower risk of
Alzheimer's dementia 53,
stronger bones with fewer fractures54, and most importantly a 50% reduction
in cardiovascular disease55,
the number one threat to women's longevity. In addition, estrogen
may be important in preventing osteoarthritis56, the most common cause of disability
in women, and also may be important in reducing the occurrence
of colon cancer57,
the third most common cancer in women. There are also the benefits
of more youthful skin, less vaginal dryness, increased libido,
and less urinary incontinence. Following a long history of postmenopausal
use in Europe, the addition of DHEA to regimens of hormonal supplementation
is now advocated as one of the most advantageous source of estrogen
Accumulation of estrogen during andropause is amplified by obesity60 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.61,62,63 The risks of elevated estrogen in men further correlate to decreased ability to dissolve blood clots.64 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.
Recent experimental work supports this connection between
healthy estrogen metabolism and men's health. In studies culturing
human vascular endothelial cells (HUVEC), it has been shown that
2-methoxy estradiol is a primary regulator of cell growth and
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, have been shown to prevent the oxidation of
Lipoprotein oxidation is now accepted as an early, initiating
event in atherosclerosis.
Copyright 1999 by Dr. Michael A. Zeligs, All Rights Reserved
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