Concerns regarding Phytoestrogens

There is a very significant misunderstanding around the consumption of phytoestrogens. The safety issues can be boiled down to three fundamental traits of phytoestrogens:

1. The binding affinities of phytoestrogens for the estrogen receptors (ERs) are significantly lower than estrogens, and

2. Phytoestrogens are not full agonists but partial agonists of ERs, lastly

3. The serum concentrations of phytoestrogens is in the nanomolar range.

1. Binding affinities of phytoestrogens

Binding affinities provide important insight into the use of phytoestrogens. Relative binding affinities (RBAs; Table 1), provide relevant understanding of the potential estrogenic effects of these compounds.

Given the values displayed in Table 1, it is obvious that, compared to estrogens, the phytoestrogens have a fraction of the affinity for the estrogen receptors (ER). For example, the highest affinity demonstrated is by equol, a metabolite of daidzein (natural occurrence in red clover is minimal at 0.0052% dry weight), which is 50 x weaker than 17β-estradiol. The next closest affinity is 8-prenylnarigenin to ER-α, which is ~70 x weaker than 17β-estradiol.  After equol and 8-prenylnarigenin, the affinities drops off substantially with the next closest compound, genistein, demonstrating 1/143 of the affinity of estrogens, while compounds such as biochanin A and formononetin do not exhibit any detectable affinity for either ER-α or ER-β.  Important to this discussion is that there is no evidence of the compounds that do not fit into the isoflavone family of compounds such as honokiol (magnolia) , diosgenin (wild yam), ginsenosides, such as RG-1 (ginseng), binding to estrogen receptors. In addition, thus far no compound in black cohosh or peony has been found to bind estrogen receptors. (apologies, unable to get the table in this format)

 

2. Phytoestrogens act as partial agonists

Key to this discussion is to recall the fundamental pharmacological principle that a partial agonist can act as an antagonist.

Partial agonists are compounds that activate a receptor, but only with partial efficacy, as compared to a full agonist that would elicit a maximal response of the receptor system. Importantly, when both a full agonist and partial agonist are present, the partial agonist acts as a competitive antagonist, competing with the full agonist for receptor occupancy and producing a net decrease in the receptor activation observed with the full agonist alone. In addition, the binding dynamics of a partial agonist often do not lead to activation of an estrogen response. Therefore, a pharmacological rule of thumb is that a partial agonist may also be considered an antagonist. 6 Clinically, partial agonists can reduce the overstimulation of receptors when excess amounts of the endogenous ligand are present. Moreover, partial agonists may not recruit coactivators essential to estrogen signaling.7,8

Phytoestrogens have been found to act as a partial agonist in a number of tissues,7,9,10 including breast tissue.11,12 Thus, as partial agonists/antagonists binding to ERs may not correlate with activation. Since ligand binding to ERs provokes a conformational change and the conformational differences depend on the chemical structures of the ligands,13,14 this may induce different cooperativities in binding. After ligand binding, ERs form a dimer, followed by interactions with the coactivators.15 Since the coactivators interact with ER by recognizing the conformation of its ligand binding domain,16 the conformational differences of ligand-bound ER, in this case phytoestrogen-ER, may lead to different interactions with coactivators and different transcriptional activities.17 This difference in conformation is dependent on the structure of the ER ligand and is an explanation as to why so many of the phytoestrogens can have anticancer activity.1,8]

Other potential activities of phytoestrogens include modulation or down-regulating of breast cancer stem cell proliferation through various pathways including Hedgehog and Wnt inhibition.  Phytoestrogens likely reduce pro-inflammatory cytokines at various pathways including NF-kB, COX-2, LOX-5, IL-6, inhibit HDAC, gene mutations in breast cancer including p53, PTEN, Bcl-2, p27, p21, myc signaling, control  growth factors such as insulin-glucose, PI3-K, mTOR, EGFR, VEGF pathways, and assist in the removal of cancer promoting toxins through pathways such as Nrf-2 up-regulation.18

In human trials classical estrogenic effects of phytoestrogens are not observed. In a clinical trial of two weeks of feeding soy with established isoflavone content (which contains the isoflavones found in red clover), no effect was seen on breast epithelial cell proliferation, estrogen and progesterone receptor status, apoptosis or mitosis.11 Additional support comes from a clinical trial observing menstrual cycle changes in which an isoflavone rich supplement induced similar changes as tamoxifen in a population of women.12

Epidemiological data shows an association between consumption of a high soy diet and a low incidence of breast cancer11,19-21 and this is suggested to be due to partial agonism.8 In a study of 16,048 subjects researchers observed that nine years after cancer diagnosis women with breast cancer in the highest intake of soy food (> 23 mg isoflavones/day), had a 9 percent reduced risk of mortality and a 15 percent reduced risk for recurrence, compared to those who had the lowest intake level. There was also no increase in risk for cancer recurrence or death among survivors of breast cancer with soy food  consumption.22 The intake, as well as serum and urinary concentrations, of phytoestrogens is also high in countries where incidence of prostate cancer is low, suggesting a chemopreventive role for phytoestrogens. Again this is likely due an antagonist effect on the endogenous estrogens in initiation or promotion of tumor formation.23

Genistein, one of the isoflavones found in red clover, is a potent inhibitor of both estrogen receptor negative and positive breast cancer cells 24and of tyrosine protein kinase activity of several growth factor receptors and oncogenes that may be associated with tumor cell growth.25 The inhibition of DNA topoisomerase II has also been suggested as an alternative mechanism for the action of isoflavones .26 Genistein is also an inhibitor of angiogenesis, which may partly explain the possible antitumor activity of phytoestrogens.23,27 Genistein was found to inhibit angiogenesis through regulation of multiple pathways, such as regulation of VEGF, MMPs, EGFR expressions and NF-κB, PI3-K/Akt, ERK1/2 signaling pathways. 28

Although, isoliquiritigenin (licorice) is considered to be a phytoestrogen, it is not an isoflavone. However, its RBA (estrogen set at 100) is 0.059. Thus, as a partial agonist, it appears to act as an antagonist. Isoliquiritigenin has shown aromatase inhibition showing a Ki of around 3. In addition it shows inhibition of growth of MCF-7 (human breast cancer) cells. In a murine model of a xenograft of MCF-7 cells, isoliquiritigenin was found to deter the xenograft growth.29

Another compound not found in the isoflavone family is honokiol (magnolia), which has been consumed for over two thousand years in traditional Chinese medicine. When honokiol is tested against human breast cancer cell resulted in a time- and concentration-dependent growth inhibition in both estrogen receptor-positive and -negative breast cancer cell lines, as well as in drug-resistant breast cancer cell lines such as adriamycin-resistant and tamoxifen-resistant cell lines.30  Honokiol has also demonstrated a reduction in angiogenesis angiogenic activities of human endothelial cells and efficiently suppresses the growth of angiosarcoma in nude mice. Honokiol was able to attenuate the PI3K/Akt/mTOR signaling by down regulation of Akt phosphorylation and upregulation of PTEN expression. Finally, the combination of honokiol with the mTOR inhibitor rapamycin presented synergistic effects on the induction of apoptosis of breast cancer cells.30

3. The serum concentrations of phytoestrogens are in the nanomolar range

There are generally very low levels of aglycone phytoestrogens (without glycoside sugars) in the circulation (< 3% of the total intake) and serum levels are in the ng/mL range. 31  The majority of phytoestrogens are absorbed and then conjugated to glucorunic acid and sulphuric acid while in hepatic circulation. 32 Thus the availability of phytoestrogens is at ng/mL or lower concentrations.

Summary of phytoestrogens review

The phytoestrogens covered here and provided, not as isolated but, in whole plant extracts, when taken orally within the therapeutic range recommended for this trial, may provide modest cancer suppressing effect along with synergistic effects with either or both pharmaceuticals proposed in this trial. There may also be protective effects from drug toxicity. These conclusions are based on animal models, human trials, and epidemiological research.  Thus far, most phytoestrogens have demonstrated pleiotropic effects on cellular signaling, kinase inhibition, cell cycle regulation, and antioxidative properties that are likely to contribute to the beneficial effects of phytoestrogens and the beneficial effects on estrogen-dependent diseases.3,33-35 After consideration of the available evidence the phytoestrogens do not appear to be a risk for breast cancer patients in light of their binding affinities, partial agonists effects and serum levels.

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