PHYTOESTROGEN BASICS

PHYTOESTROGEN BASICS
© Dr Jillian Stansbury

Phytoestrogens are natural compounds from plants that are able to bind to estrogen receptors and elicit a variety of hormonal effects. Because many types of breast and prostate cancer involve altered and excessive hormonal stimulation of these organs, phytoestrogens may be an important tool for improving hormonal balance in these cancers.

 
Embryologic development of the breasts, prostate and reproductive organs involves both estrogens and androgens. Exposure to some exogenous estrogens in the neonatal period, such as hormonally active synthetic chemicals may increase the risk of hormone related cancers later in life, while natural plant based compounds such as the phytoestrogens may reduce the chances of hormone-related reproductive cancers later in life. Steroidal metabolism and signaling may be “disrupted” early in life through exposure to hormonally active synthetic chemicals. This phenomenon is being referred to as “Endocrine Disruption.” On the other hand, phytoestrogens may mitigate the severity of endocrine disruptors and offer positive hormonal influences on the breast and prostate. Furthermore, genes that control cellular and hormonal receptor quantities and response are also shown to unfavorably influenced by exogenous chemicals , and favorably influenced by phytoestrogens.

Phytoestrogens as Selective Estrogen Response Modifiers
There are multiple types of estrogen receptors, including alpha and beta, and these two types seem to counteract and balance one another. In general, the alpha subtype directs cellular proliferation while the beta subtype directs differentiation and apoptosis. Intensive research is underway to develop therapies that target specific subtypes of receptor, specific to individual tissue types as a means of treating estrogen dependant cancers and disease. These therapeutic agents are referred to as SERMS – Selective Estrogen Response Modifiers. For example genistein, an isoflavone type of phytoestrogen common in legumes is an estrogen receptor agonist, particularly to the beta subtype, and thus could be considered to be a natural SERM. Although plant phytoestrogens exert effects on the reproductive organs, research suggests they are protective and of positive benefit when consumed in normal dietary levels, rather than disrupting to endocrine balance as are so many synthetic chemicals. Genistein is one of the most active and most studied of the isoflavone phytoestrogens. Genistein may also affect gene expression due to direct activity at estrogen receptors. For example, prolonged exposure to genistein in early life is reported to reduce prostate size and may reduce the risk of BPH and prostate cancer later in life. Studies have shown genistein to improve the response to irradiation in estrogen positive cancers, to have inhibitory effects to prostate cancer cell lines, to have positive influences on steroidal producing genes, and to activate several genes associated with tumor suppression. Supplementation with isoflavones in dosages that exceed typical dietary amounts has been noted to slow the progression of prostate cancer and have no noticeable side effects or toxicity. One study treated men with recurrent prostate cancer with isoflavones in the form soy milk quantified to deliver a standardized amount of genistein, dosed 3 times a day for 1 year. For nearly all men, serum equol was increased, and for many men the upward trend of PSA levels was either stabilized or in some cases reversed.

The Amphoteric Action of Phytoestrogens
When phytoestrogens bind estrogen receptors they act variably, as either agonists or antagonists, depending on the physiologic situation. Phytoestrogens have such varying activity and ligand affinity for the various tissues and receptor subtypes of estrogen that they may be the ideal “SERMs”. For example, isoflavones might act as weak agonists in situations of low estrogen in the body, yet that weak agonism can compete with the body’s own estrogens in a high estrogen load situation and reduce estrogenic stimulation. This dual action of phytoestrogens, to both offer estrogenic support and reduce excessive estrogen stimulation in the body is referred to by herbalists as “Amphotericism”. Inclusion of isoflavones and other phytoestrogens in the diet or in the form of herbal supplements is thought to offer many health benefits including protection against hormone-related cancers.  Synthetic phytoestrogen-like compounds have been tested and interestingly display no such amphoteric action.

PHYTOESTROGENS AND HORMONAL ENZYME SYSTEMS
The specific steroidal enzyme systems affected by phytoestrogens include the aromatase, dehydrogenase, reductase and sulphotransferase enzymes and all may have benefits for hormone related cancers.

The Sulfotransferases. Sulfotransferases are phase II detoxifying enzymes found in the tissues. The sulfotransferases add atoms of sulpher to estrogens rendering them less active as sulfated estrogens do not bind estrogen receptors. Estrogen sulfotransferases are more active in healthy breast cells than in cancer cells and the ingestion of phytoestrogens such as genistein, quercitin, resveratrol and other flavonoids have been shown to promote the sulfotransferases.

The Dehydrogenases The 17-beta dehydrogenase family of enzymes is responsible for oxidizing steroids making them less active and controlling the amount of active hormones circulating in the blood stream. There are at least 15 subtypes of dehydrogenase enzymes and breast cancer, prostate cancer and endometriosis involve imbalances of these enzymes and the hormones that they regulate. Many phytoestrogens including flavonoids, coumarins, and coumestans are noted to inhibit 17-beta dehydrogenase .  Licorice for example, Glycyrrhiza glabra, contains genistein and other phytoestrogens and inhibits numerous types of dehydrogenases.
Alpha-5 Reductase Inhibitors Alpha-5-reductase is the enzyme that converts testosterone into the more active dihydrotestosterone. Because dihydrotestosterone is noted to have greater stimulatory and proliferative effects on the prostate gland compared to testosterone, inhibition of this enzyme is a present therapy in the management of prostate enlargement and cancer. Finasteride (Prosgar) is a synthetic pharmaceutical used for this purpose. Genes the control 5alpha-reductase in the prostate are induced by high fat diets and inhibited by genistein. Serenoa repens, Pygeum africanum, Urtica and Green Tea, Camellia sinensis catechins are botanical agents noted to inhibit alpha-5-reductase activity. Serenoa repens is noted to inhibit tumorogenisis and induce apoptosis in animal models of prostate cancer. Human investigations have confirmed the ability of Serenoa to inhibit alpha5 reductase and reduce circulating levels of active testosterone.
The Aromatase Inhibitors Aromatase enzymes turn circulating estrogens androgens into active estrogen and research is ongoing to investigate the effects of pharmaceutical and natural aromatase inhibitors as a therapy for breast and prostate gland. Aromatase enzymes are abundant in peripheral lipid cells, but have also been demonstrated in high amounts in prostate cells themselves. Many coumarin-type phytoestrogens common in legume plants have been shown to inhibit aromatase, such as the legume member Glycyrrhiza.

 

Phytoestrogens for Reproductive Cancers
This review suggests that phytoestrogens offer a positive influence on hormonal balance when included in the diet on a regular basis, as early as in utero. Phytoestrogens also appear to be valuable tools to include in the overall treatment protocols for breast, prostate and other hormonal cancers. Although they can exert weak estrogenic effects themselves, the research is mounting that such hormonal actions do not stimulate hormone dependent cancers but rather serve to block or mitigate the body’s endogenous hormones via effects on hormone receptors, enzyme systems that process hormones, and effects on hormone regulating genes within the cells.
Because the research is still broad and varied in approach, it is still too early to nail down specific dosage regimens or precise treatment strategies for reproductive cancers using phytoestrogens. Only a decade ago the use of phytoestrogens at all for cancer patients was controversial and of concern to practitioners due to valid concerns over possible proliferative effects on hormone sensitive tissues. The purpose of this review is share the progress being made in determining the safety of phytosterol consumption, and even therapy for patients with hormonal cancers. Not only is the data weighing in on the side of safety for phytosterols, they appear to have preventative and clinical benefits for breast and prostate cancer patients. It appears that legume and phytosterol consumption by pregnant women may be of benefit to the hormonal balance their offspring, and that regular consumption of phytosterol-containing whole foods over a lifetime is to be encouraged.

 

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