Effects of genistein:
- Weak estrogenic effect – estrogenic activity is one-third that of glycitein and four times more active than daidzein.
- Anticarcinogenic effect – genistein inhibits cell proliferation of various tumor cells, especially in the prostate, by promoting apoptosis (programmed cell death).
- Inhibition of topoisomerase II – this enzyme is able to cleave DNA and introduce additional turns into the DNA double strand, thereby changing the topology of DNA molecules
- Inhibition of various protein tyrosine kinases, for example, EGF receptor kinase.
- Inhibition of angiogenesis – angiogenesis distinguishes the growth of small blood vessels – capillaries – predominantly by sprouting from a preformed capillary system; angiogenesis is of considerable biological and medical importance, especially in tumorigenesis, because tumors depend on a co-growing capillary network that supplies the tumor with oxygen and nutrients
- Activation of the “Peroxisome Proliferator-Activated Receptor” – PPAR-y.
- Antioxidant activity – genistein inhibits lipid peroxidation.
- Antithrombotic effect – genistein prevents the activation as well as aggregation of platelets (blood platelets) and regulates the widening of blood vessels; prevents plaque formation.
- Prevents bone loss, increases bone density.
Caution!Excessive intake of genistein leads to adverse effects. There is evidence that the isoflavone in higher doses has genotoxic potential and can damage the genetic material. At concentrations between 10 and 100 µM, gene mutations, DNA strand breaks, or chromosomal aberrations, among others, may occur. Some studies reported that newborn mice given genistein at high doses under the skin had an increased rate of adenocarcinomas (carcinomas growing with a glandular structure) of the uterus (womb) in adulthood.
- Weak estrogen activity – the highest activity of soy isoflavones[13, 17]
Scientific studies
Most studies have been conducted with all three substances combined. For this reason, the following effects are related to isoflavones in general.
Anticarcinogenic effects
An isoflavonoid-rich diet high in soybean products may significantly reduce the risk of cancer. Due to their estrogen antagonistic effects, phytoestrogens are able to protect against hormone-dependent tumor types, such as mammary (breast), endometrial (endometrial), and prostate cancers [1, 8 ,19, 23, 30]. Via their low estrogenic effect at the receptor, they lead to a slowing of estrogen-induced cell division and, at the same time, to growth inhibition of genetically modified cells of the breast, endometrium and prostate. Using different animal models, it could be demonstrated that feed supplemented with genistein inhibits the growth of androgen-dependent prostate carcinoma cells in early stages. Genistein induces apoptosis (programmed cell death) for this purpose. In relation to this, clinical studies showed that in men with prostate carcinoma (prostate cancer), the rate of apoptosis was significantly increased in prostate tumor cells with low to moderate aggressiveness after ingestion of 160 mg of isoflavones for an average of 20 days. Furthermore, isoflavonoids can stimulate the synthesis of sex hormone binding proteins, especially SHBG – sex hormone binding globulin – in the liver [6, 8, 23,]. The higher the concentration of these proteins, the more sex hormones can be bound and the lower the concentration of biologically active estrogens and also androgens. Watzl and Leitzmann were also able to establish anticarcinogenic effects of phytoestrogens independently of the hormone-related effects. According to international cancer statistics, hormone-dependent tumor diseases occur much less frequently in Asian countries, where soy is an essential part of the diet, than in Western industrialized countries.
Mammary carcinoma (breast cancer)
A case-control study from Japan demonstrated that diets containing soybean products were associated with a reduced risk of breast cancer in premenopausal women. However, other epidemiological studies showed no protective effects of phytoestrogens with respect to breast carcinoma.In a large-scale cohort study (n > 70,000), higher overall soy intake was associated with a significantly lower risk of breast cancer. In premenopausal women with high soy intake, the risk was 54% lower. An evaluation related to hormone receptor status showed a risk reduction for estrogen receptor-negative and progesterone receptor-negative breast carcinomas in premenopausal women and for estrogen receptor-positive and progesterone receptor-positive breast carcinomas in postmenopausal women. However, as there are not yet sufficient study results on breast cancer prevention with isoflavones – randomized clinical trials are lacking – the use of isoflavones for breast cancer prevention seems premature at the present time. Further study results should be awaited. Caution!Isoflavones should not be taken in high doses in cases of existing estrogen receptor-positive breast cancer, precancerous changes in the breast, or a genetic predisposition! There is evidence that in affected women the intake of phytoestrogens exerts a stimulating effect on the growth of tumor cells in the breast. It is highly probable that the timing of phytoestrogen exposure plays a decisive role in the influence on tumor development. Animal studies showed that the strongest protective effect was present when the animals ingested phytoestrogens during breast development and thus early in life. One explanation for this could be that genistein, due to its estrogenic effect, causes an early or premature differentiation of the mammary gland tissue, which then reacts less sensitively to chemical carcinogens such as benzo(a)pyrene, acrylamide, aflatoxins or benzene. In postmenopausal women (women after menopause) without existing breast carcinoma, taking isoflavone-containing supplements has no adverse effects on the mammary gland (European Food Safety Authority (EFSA):
- No increased risk of mammary carcinoma (breast cancer).
- No increased tissue density in mammography (X-ray examination of the breast).
- No effects on the expression (release) of the proliferation marker KI-67 (synonym: MIB1, proliferation marker for objectification and validation of grading; allows conclusions about growth behavior).
The amount of isoflavones from soy should be limited to a maximum of 100 mg per day and the duration of intake up to 10 months.
Antioxidant effects
Isoflavones are effective as antioxidants in both water-soluble and lipophilic systems due to their chemical structure. They exert antioxidant effects on lipoproteins and blood lipids, among others, and thus prevent lipid peroxidation. Finally, a high intake of isoflavone-rich foods protects against reactive aggressive oxygen radicals, such as singlet oxygen, which promote the oxidation of nucleic acids, various amino acids in proteins, and unsaturated fatty acids and thus the development of atherosclerosis (arteriosclerosis, hardening of the arteries) and cancer.
Immunomodulatory effects
Due to the expression of estrogen receptors on various immune cell types, phytoestrogens may influence the immune system. Quite a few studies have demonstrated the immunosuppressive effects of isoflavones. First intervention studies with flavonoid-rich fruit juices from a mixture of different fruit species led to an increased cytokine synthesis – especially interleukin-2 – and stimulation of further lymphocyte functions. Lymphocytes belong to the group of leukocytes (white blood cells) and produce antibodies that recognize foreign substances, such as bacteria and viruses, and remove them by immunological methods. In addition, lymphocytes are responsible for the production of messenger substances, especially cytokines. Interleukins are used for the communication of immune defense cells (leukocytes) among each other in order to fight coordinated pathogens or even tumor cells. Further studies show that physiological concentrations of daidzein – 0.1 to 10 µM – contribute to the stimulation of lymphocyte proliferation in a dose-dependent manner, whereas high genistein concentrations – >10 µM – lead to an inhibition of immune function. Excessive isoflavone intake is therefore not recommended. Physiological uptake of phytoestrogens, especially genistein as well as genistein and daidzein glucuronides promote the activation of human natural killer cells.
Antithrombotic effects/cardioprotective effects
Epidemiologic studies have demonstrated that flavonoid intake is inversely correlated with cardiovascular disease mortality risk. High flavonoid intake reduced the risk by approximately 33% compared to low intake. An improvement in the cardiovascular risk profile was also shown for isoflavones. The reduction in coronary heart disease (CHD) risk was mainly due to a reduction in LDL cholesterol and possibly an increase in HDL cholesterol. LDL cholesterol – low-density lipoprotein cholesterol – represents the “bad” cholesterol because it is deposited on the inner layers of the vessels when there is an excess of cholesterol and is therefore considered a risk factor for atherosclerosis. The higher the LDL cholesterol content in serum, the higher the risk of developing atherosclerosis (arteriosclerosis, hardening of the blood vessels), for example, resulting in a myocardial infarction (heart attack). In 34 of 38 epidemiological studies, the cholesterol-lowering effect of isoflavones could be determined. In other studies, the intake of soy protein – usually 20 to 60 g/d for 4 to 12 weeks with isoflavone levels between 50-150 mg/d – resulted in a lowering of LDL cholesterol as well as triglycerides in serum – lipids and lipoproteins in the blood. Furthermore, due to their antioxidant properties, isoflavonoids prevent oxidation of LDL and increase arterial elasticity. By inhibiting the activation as well as aggregation of platelets (thrombocytes) and regulating the widening of blood vessels, genistein in particular can counteract the formation of a thrombus (blood clot). In addition, genistein prevents the migration and proliferation of cells in the muscles that contribute to plaque formation. Furthermore, it is hypothesized that the level of apple consumption may also influence blood clotting. This hypothesis was confirmed by epidemiological studies. Individuals with a high apple intake showed a significantly reduced risk of cardiovascular disease.
Effects on the menstrual cycle
Research indicates that a diet high in isoflavonoids leads to a prolonged menstrual cycle in premenopausal (menopausal) women. This phenomenon can be explained by the altered hormone metabolism. Climacteric complaints (menopausal complaints)
Furthermore, it was shown that the intake of isoflavones can alleviate menopausal symptoms. It is known that Japanese women have a much more balanced hormonal situation than European women due to regular consumption of soy. Incidentally, the Japanese language has no equivalent for the term “hot flashes”!
Other effects – osteoporosis
Phytoestrogens may have an influence on bone metabolism. Possibly, isoflavones, among others, prevent bone resorption and increase bone density, which could inhibit the development of osteoporosis. Administration of 60 to 70 mg of isoflavones daily in the form of soy products for 12 weeks in postmenopausal women resulted in a significant decrease in the activity of osteoclasts – bone-degrading cells – and increase in the activity of osteoblasts – bone-building cells. Despite these positive results, some studies also show no preventive effects of isoflavones in relation to the development of osteoporosis. In particular, in pre-menopausal women, isoflavone intake had no effect on bone density. Therefore, based on the currently available data, it is premature to speak of a protective effect of isoflavones against osteoporosis. Finally, further studies with larger subject collectives as well as longer study periods are necessary to definitively answer this question. Since there is not only one secondary plant compound present in food plants, but a mixture of hundreds of secondary plant compounds, it is highly likely that the protective effects are due to a cumulative or synergistic effect of the variety of bioactive compounds. At present, however, it is still unclear whether secondary plant compounds can only exert their maximum protective effects in interaction with the essential nutrients and dietary fiber present in vegetables and fruits.Finally, for these reasons, it is not currently possible to provide information on the optimal intake of phytochemicals.