Estrogen Inhibitors - Overview and Science

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There is much confusion today as to what really promotes estrogen and what doesn't. The purpose of this addendum is to provide science overview of some of the most important and controversial estrogen inhibitors.

. . .certain compounds in plants called flavonoids and indoles can exert various biological effects, including antioxidant, anti-carcinogenic, anti-estrogenic and modulation of sex hormones.

Flavonoids

It has been widely established that certain compounds in plants called flavonoids can exert various biological effects, including antioxidant, anticarcinogenic, anti-estrogenic and modulation of sex hormones. Flavonoids are a group of polyphenolic phytochemicals that include flavones, isoflavones, isoflavonones, catechins and chalcones, among other chemicals. They occur in relatively high concentration in fruits, vegetables, nuts and grains. Flavonoids are known to have widely diverse beneficial biological effects, such as anti-inflammatory (Middelton, 1998), antioxidant (Pletta, 2000), antiviral (Jassim and Naji, 2003), and anticancerous (Alercreutz, 2002; Frei and Higdon, 2003; Rietveld and Wiseman, 2003). They also modulate the function of sex hormones and their receptors.

Estrogen Promoters vs. Estrogen Inhibitors

Certain flavonoids, such as the isoflavone genistein (found in soy) are estrogenic (Wang et al, 1996; Zand et al., 2000), whereas others, such as 5.7 dihydroxyflavone (chrysin) are anti-estrogenic and can interfere with steroid hormones synthesis and metabolism.

Note that estrogen promoting compounds are often called phytoestrogens. However, only a limited number are in fact estrogen receptor agonists (estrogen mimickers). In contrast, many flavonoids are known to interfere, to a greater or lesser degree, with various cytochrome P 450 enzymes (enzymes involved in steroid hormones synthesis) including those involved in steroid hormone synthesis.

Several studies have addressed the ability of flavonoids to interfere with the activity or expression of aromatase (cytochrome P 450 19 cyp19), the enzyme responsible for the conversion of androgens to estrogens (Ibrahim and Abul-Hajj, 1990; Kellis and Vickery, 1984; Le Ball et al., 1998; Whitehead and Lacey, 2003). These studies revealed significant differences in the relative inhibition potencies of flavonoids. For that matter, cellular uptake and metabolism capacity of flavonoids as well as their tissue specific affinity needs to be considered.

Aromatase inhibition of flavonoids

The ability of various natural flavonoids to inhibit aromatase activity was investigated and documented. For example, quercitine (abundant in onion and garlic) was found to inhibit human aromatase activity in plancental microsomes (Kellis and Vickery, 1984). The ranking of relative inhibition potencies differed among tissues tests, although some general trends are apparent. In certain cancerous cells (plancetal chorlocarcinoma cells), apigenine (derived from chamomile) was more potent than hydroxyflavone, chrysin (derived from passiflora), naringenin (derived from grapefruit) and quercitine. On the other hand, in normal human plancetal cells, 7 hydroxyflavone and chrysin were more potent than apigenine, naringenin and quercitine. In general, studies show that flavones (chrysin, apigenine) were more potent aromatase inhibitors than flavonones (7 hydroxyflavone or naringenin), a finding that is consistent with previous reports (Le Bail et al., 1998; Sorrinen et al., 2001).

Researchers have found no effect of 7 methoxyflavone and flavonone on aromatase inhibition. For that matter, products containing methoxylated flavones that were previously introduced to the fitness industry failed to provide any substantial estrogen inhibitory benefits.

Aromatase induction by flavonoids

The human aromatase enzyme is known to be under the control of several tissue-specific promoters (Bulun et al., 2003; Harodo et al., 1993; Simpson et al., 1993). For example, aromatase in human gonads is regulated through promoter p 11 and 1.3, both of which are stimulated by cAMP dependent protein kinase A (PKA) second messenger pathway. Healthy breast adipose stromal tissue utilizes promoter 1.4, which is stimulated by glucocorticoid (cortisol) signaling pathway. However, in malignant breast tumors, a promoter switch appears to occur, resulting in strongly increased in promoters pll and 1.3 activity (Agrawald etal.j1996, Kamatetal., 2002) Researchers believe that the above promoters are therefore important in aromatase regulation in gonads and breast tumors.

. . . certain flavones that cause fat loss in animal studies may induce aromatase activity in humans.

Dutch researchers have found that certain flavones that cause fat loss in animal studies may induce aromatase activity in humans. For instance, the isoflavone genistein has shown to increase intracellular cAMP concentrations and thus cause elevation of cAMP mediated p II and I.3 promoter specific mRNA levels. The researchers indicated that aromatase inducing isoflavones are known to be phosphodiestrase inhibitors in several tissues. Phosphodiestrase is the enzyme that metabolizes cAMP, thus lowering its cellular level. Inhibition of phosphodiesterase will sustain high levels of cAMP, a cellular factor that induces fat breakdown in adipose tissue. Both quercitin and genistein have been shown to stimulate cAMP medicated Lypolsis in rat adipocytes (Kuppusamy and Das, 1992). However, they also show to induce aromatase activity in cancer cells. Quercitine, however, was found to be an aromatase inhibitor in healthy cells or when applied to cancer cell in high concentration.

Note that forskolin (derived from coleus as forskolii), a compound used by the fitness industry to promote fat loss, should be of concern. Forskolin is in fact a potent estrogen promoter due to its cAMP stimulating and aromatase inducing effects. Researchers have been using forskolin as a standard aromatase promoting agent for comparative purposes.

Balancing estrogen promoters with estrogen inhibitors

Scientists believe that as the human diet contains several flavonoids with aromatase inhibitory properties in various concentrations, it may be possible for combined tissue concentrations to be reached via proper supplementation, and thus result in a certain degree of aromatase inhibition.

It has been therefore suggested that consumption of high concentrations of potent aromatase inhibiting compounds (more than 100 times the typical diet) may result in high concentrations of single flavonoids, sufficient enough to inhibit aromatase activity.

Nonetheless, under normal dietary conditions, flavones occur in complex mixtures, with often contradictory effects (inhibiting as well as promoting) on the aromatase enzyme and estrogen metabolism. It has been therefore suggested that consumption of high concentrations of potent aromatase inhibiting compounds (more than 100 times the typical diet) may result in high concentrations of single flavonoids, sufficient enough to inhibit aromatase activity.

Inhibition of aromatase activity in individuals suffering from over estrogenic activity due to exposure to chemicals, hormonal therapy or aging, may help reduce the risk for cancer and may also help eliminate estrogen related fat gain.

Recent studies at the Medical University of South Carolina, Charleston, South Carolina lead researchers to the conclusion that , flavones work better when combined together to provide total body (systemic) aromatase inhibition and defense against estrogen. Flavones, such as chrysin, apigenine and galangin (ingredient in bee propolies) showed various inhibition and different affinities (potencies) towards the two human cytochrome P450 aromatase enzymes: 1A1 and 1A2. Therefore, combining anti aromatase flavones together will most likely grant a superior total body estrogen inhibiting impact by virtue of addressing various tissue specific ratios of CYP 1A1 / CUP 1A2.

Biochemical mechanisms of aromatase inhibition potencies of flavonoids

It has been established that the most important contributor to the aromatase inhibitory effect of flavonoids is the 4-oxo group on the c ring of the flavone base structure (Kao et al., 1998). Hydroxylation of the 7-position on the A-ring enhances the inhibitory potency considerably (such as with 7 hydroxy flavone and chrysin-5, 7 dihydroxyflavone). Scientists did not observe a dramatic difference in potency when comparing 7 hydroxy flavone with 5, 7 dihydroxyflavone. As noted, it has also been established that flavonones such as naringenin (from grapefruit) have lower aromatase inhibitory potency than flavones. It is plausible that the lack of 2, 3 double-bond in the flavonones results in reduced electro-negativity of the 4-oxo group and subsequently, a weaker interaction of this group with the heme prosthetic group of the aromatase enzyme.

The mechanism by which isoflavones such as those found in soy fail to exhibit aromatase inhibition capacity is attributed to the fact that when flavonoids structures are substituted on the 3 position of the c-ring, as was observed for genistein; there is a consequent obliteration of aromatase inhibition capacity. This is consistent with the very weak or non-existent inhibitory effects of these compounds found in studies. (Campbell and Kruzer, 1993; Kao et al., 1998; Polissero et al., 1996; Saarinen et al., 2001)

Aromatase inhibiting potency values of natural flavonoids

In a recent review – Toxicological Sciences 82, 70-79 (2004), researchers at Utrecht University, Netherlands, and the University of California, Davis, CA, have published a comparative database of aromatase inhibiting potencies by natural flavonoids.

Various classes of naturally occurring flavonoids including flavons, flavonones, isoflavones and catechins were tested for their effects on aromatase activity and cell viability in human adrenocortical carcinoma cells.

Among the flavones, 7 hydroxyflavone, chrysin and to a lesser degree, apigenine have shown aromatase inhibiting activities in concentrations of about 4, 7 and 20 µM respectively (micron µM – 0.001 milliliter), values that were well below concentrations that caused the first sign of cutotoxicity. The first statistical signs of significant decreases in cell viability of about 20% were observed at 30 µM for chrysin, and at 100 µM for 7-oh flavone and apigenine. 7 methoxyflavone had no statistically significant effect on aromatase activity at concentrations up to 100 µM, a concentration at which the first statistically significant decrease in cell viability of about 30% was observed.

The flavonones were considerably less potent aromatase inhibitors than the flavones. 7-hydroxyflavonone and naringenine had aromatase inhibiting potencies values close to the high concentrations of 100 µM, a concentration at which both compounds cause a 20% decrease in cell's viability. 7 methoxyflavonone had no effect on aromatase activity but nonetheless caused 15% decrease in cell's viability at a cellular concentration of 100 µM.

Finally, the flavonoids catechins and epicatechins (found in green tea) have shown no aromatase inhibiting potencies. Both flavonoids have shown no cellular toxicity effects.

CLA

A certain compound in dairy has shown to possess anti-estrogenic and anticarcinogenic properties. Called CLA (conjugated linoleic acid), this compound is an ingredient in milk fat, with higher levels found in milk derived from grass-fed cows. CLA is also found in human mothers' milk. Statistically, high levels of CLA in breast milk has been found to be correlated with decreased cancer incidence in both mothers and their offspring. Australian researchers found that consumption of CLA significantly reduced circulating LDL cholesterol in humans. CLA was found to inhibit a certain protein (called apolipoprotein B 100), responsible for the production of LDL cholesterol in the liver.

Studies at Bassett Research Institute, Cooperstown, New York, revealed that CLA decreased tumor growth in animals. Other studies at the University of Alberta, Edmonton, Canada, have shown that CLA can destroy cancer cells in humans. Both CLA and omega 3 oil (N-3) were found to interfere with tumor cell cycles and induce apoptosis (cell suicide) in cancer cells.

Scientists believe that CLA works via similar mechanisms as N-3. The evidence to the anti-estrogenic/anti-carcinogenic properties of CLA is substantial. Recent studies at the University of Texas, Department of Medicine/Clinical Immunology indicated that CLA directly inhibits the growth of human breast cancer cells. CLA selectively inhibited proliferation of estrogen receptor positive (ER+) breast cancer cells.

Studies at Emory University, Georgia, USA, provided evidence that the anti-estrogenic activity of CLA is caused by inactivating estrogen receptors. Previous studies showed that CLA can inhibit estrogen related transcriptional activity in the genes, and thereby induce an anti-tumor effect on breast cancer cells.

CLA actually comprises of a group of conjugated fatty acid isomers with a variety of biological effects. One notable effect is the reduction of body fat in animals. It has been suggested that the active isomers regarding weight loss is the trans-10, cis-12 (t10c12) and the cis-9, trans-11 (c9t11). Studies in humans, however, indicated that even though CLA might slightly decrease body fat, particularly belly fat, there is no evidence that CLA affects body mass index or body weight in humans. Moreover, scientists at the University of Uppsala, Sweden, found that the same CLA isomer that induces fat reduction in animals, unexpectedly caused insulin resistance in humans. Though, the evidence isn't yet conclusive and more studies are needed to investigate the effect of CLA on insulin sensitivity. Interestingly, researchers at Friedrich Schiller University of Jena, Germany, found that the same CLA isomer that has been suspected of causing insulin resistance – CLA cis-9, trans-11 (c9t11) isomer, also called rumenic acid, inhibits the growth of leukemia cells.

In conclusion, studies have shown that CLA isomers have demonstrated profound anti-estrogenic and anti-cancerous effects. However, CLA failed to induce substantial fat loss in humans and it may also adversely affect insulin sensitivity. New studies are required to examine isomer-specific effects of CLA in animals and humans.

Flaxseed's lignans

There is substantial evidence that flaxseed and its lignans (components in the fiber) inhibit estradiol carcinogenic effects.

Researchers at the Division of Oncology, Faculty of Health Sciences, University Hospital, Linkoping, Sweden, found that certain phytoestrogens in flaxseeds (enterodiol and enterolactone) counteracted the effects of estradiol (E2) and thereby inhibited the growth and angiogenesis (growth of blood vessels) in solid tumors in mice. Both flaxseed phytoestrogens (lignan derived) decreases the secretion of VEGF – vascular endothelial growth factor – in human breast cancer cells.

The researchers concluded that flaxseed and its lignans have potent anti-estrogenic effects on estrogen receptors positive breast cancer and may prove to be beneficial in breast cancer prevention in the future.

Sesame's lignans

Sesame ingestion has been shown to improve blood lipids in humans and provide antioxidative effects in animals. Sesamin, a sesame lignan, was recently reported to be converted by intestinal microflora to enterolactone, the same phytoestrogen (metabolite) that has been derived from flaxseed lignans. Studies at the Department of Human Development and Family Studies, National Taiwan Normal University, Taipei, Taiwan, have shown that sesame ingestion benefited post-menopausal women by improving blood lipids, antioxidant status and possibly sex hormones status. Most notable was the dramatic increase (72%) in urinary 2 hydroxyestrone, which is the highly beneficial “anti-estrogenic” metabolite of estrogen. High levels of 2 hydroxyestrogens have been correlated with a lower risk for estrogen related cancer in women and men. For that matter, sesame phytoestrogens were found to provide similar beneficial anti-estrogenic effects as cruciferous indoles (in broccoli, cauliflower and cabbage) by shifting estrogen metabolism to favor the production of beneficial “anti-estrogenic” metabolites, rather than harmful estrogen metabolites.

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Defend your body against the harmful effects of excess estrogens with The Anti-Estrogenic Diet.

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