AGGRESSIVE STRENGTH ARTICLES
Estrogen Inhibitors - Overview and Science
By Ori Hofmekler
It has been widely established that 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 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.
... certain compounds in plants called flavonoids and indoles can exert various biological effects, including antioxidant, anti-carcinogenic, anti-estrogenic and modulation of sex hormones.
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, 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 or tobacco), 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).
Recent studies at Utrecht University, Holland, 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.
In recent reviews, scientist from Utrecht University, Holland and the California University, Davis, California reveal that certain flavones that cause fat loss in animal studies may induce aromatase activity in humans. Both quercitine and genistein increased intracellular cAMP concentrations and thus elevated cAMP mediated p II and I.3 promoter specific mRNA levels. The researchers indicated that these 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, can 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. Forsklin is in fact a potent estrogen promoter due to its cAMP stimulating and aromatase inducing effects.
Balancing estrogen promoters with estrogen inhibitors
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.
However, under normal dietary conditions, flavones occur in complex mixtures, with often contradictory effects (inhibiting or 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 in a stack 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 in a stack will most likely grant a superior total body estrogen inhibiting impact by virtue of addressing various tissue specific ratios of CYP 1A1 / CUP 1A2.
