Estrogen is one of the main hormones in the female body, but, unfortunately, after about 37 years, its level begins to decline. From this time on, aging processes become noticeable: skin tone decreases, wrinkles begin to form, because it is estrogens that regulate the activity of collagen synthesis, the main structural protein of the body. By about 45 years of age, sex hormones become so scarce that their deficiency begins to clearly affect the internal and external state of a woman. It is logical to assume: in order to maintain health, youth and beauty, estrogen must be taken from somewhere. And here phytoestrogens and synthetic estrogen (hormonal therapy) come to our aid.
“Phytoestrogens are plant compounds that are close in molecular structure and chemical action to the main estrogens of the female body - estradiol and estrone,” says Tamara Gelashvili, endocrinologist, therapist, andrologist and expert of the Lignarius brand . “They interact with the same receptors, but their influence is less than that of “natural” ones. Phytoestrogens can also have an anti-estrogenic effect - reduce the effect of female sex hormones on the body. Like other hormones, estrogens bind to receptors according to the key-lock principle, when the protrusions and depressions in the spatial structure of the hormone exactly correspond to the “relief” of the receptor. Thanks to this, hormones “recognize” and activate the necessary receptors. Phytoestrogens are close in structure to real estrogens, so they sometimes manage to activate their receptors, playing the role of a “master key” to the lock.”
Hormones against osteoporosis - a story of trial and error
Since 1938, hormone replacement therapy (HRT) has been used in the United States to combat health problems associated with menopause, including osteoporosis. At first everything went well, but side effects forced scientists to reconsider their attitude to this method. In 1975, British experts stated that hormone treatment increases the risk of uterine cancer by 40%. Therefore, researchers began to look for new ways. In the USA they decided to use genistein, a soy phytoestrogen.
And observation of the residents of Southeast Asia helped soybeans become part of the medical market. They are known to rarely suffer from heart disease and osteoporosis, with soy being an important part of their diet. However, today scientists say that this plant is overrated, because it is a mistake to draw conclusions about its exceptional value based on one factor - nutrition. Health is also influenced by climate, traditions and habits.
Genistein's finest hour came in the early 2000s, when drugs for osteoporosis with this component were developed. But over 20 years, studies of the substance have accumulated that have shaken the image of an impeccable fighter against osteoporosis. The fact is that genistein acts contradictory - sometimes it behaves like estrogens, and sometimes it blocks them.
What foods and herbs contain phytoestrogens?
Phytoestrogens are found in many foods, supplements, and even essential oils. Here are just a few of the foods that contain plant estrogen:
- Soybeans and soy products;
- Flax-seed;
- Oats;
- Barley;
- Lentils;
- Sesame seeds;
- Apples;
- Carrot;
- Wheat germ;
- Coffee;
- Liquorice root;
- Beer.
Some foods that increase estrogen levels should be taken with caution. But soy is the most concentrated food containing phytoestrogens, so it's important to know how to safely consume soy and soy products. Unfermented soy contains a long list of questionable substances that should be avoided, while fermented soy is an excellent probiotic food.
It is best to eliminate all soy milk, soy protein, and other forms of soy from your diet, with the exception of soy lecithin, a fermented soy product that has many health benefits if not consumed in excess.
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Genistein may cause infertility in women
A 2008 study from the University of North Carolina (USA) dealt a significant blow to the authority of genistein. A scientific paper describing the experiment was published in the journal Neurotoxicology. Its authors tested the effect of genistein . Animals were studied from birth to the birth of their young. We conducted a series of experiments and found that the substance has a destructive effect on the hypothalamus, the part of the brain that ensures ovulation and puberty.
More precisely, genistein inhibited the production of gonadotropin-releasing hormone , the amount of which increases during egg maturation. And this seriously increases the risk of infertility.
Also, the animals began to experience menstrual irregularities early. If we project the situation onto a person, then taking the substance can cause early menopause. Another undesirable effect of taking genistein is early puberty. Study author Dr. Heather Patisaul H. believes that soy phytoestrogen will act in a similar way in humans.
The study indicates that genistein is able to cross the placental barrier. If a woman took the substance while she was pregnant, then it will also enter the child’s body. This will lead to a surge in hormones in the latter after a few years.
Patisol’s colleagues Sandra Losa and Karina Todd (Losa S., Todd K.) from the same university continued to study the downside of genistein. Researchers have found that this soy isoflavone disrupts the development of the ovaries.
It would seem that drugs with this substance are taken by women who are already beyond childbearing age, and therefore they have nothing to fear. However, this argument is not as convincing as it seems. Some women start taking dietary supplements with genistein before menopause - to prevent diseases. And if you consider that more and more women are giving birth after 40 years, then the danger is really high.
So, genistein can provoke early menopause, which threatens to reduce the strength of bone tissue. Therefore, in principle, there can be no talk of its effective counteracting osteoporosis.
Genistein and male infertility – the connection has been proven
Soy-based medications for osteoporosis contain phytoestrogens, which makes them impossible for men to take because these substances interfere with testosterone production. And without it, a full life for the male part of the population is impossible.
Meanwhile, osteoporosis poses a threat to the stronger sex, and therefore they need a drug that strengthens bones. According to WHO statistics, almost 20% of men suffer fractures due to this disease. Can a man take the drug with genistein? If he decided to forget about childbearing forever, then the answer will be in the affirmative.
Dr. Jorge Chavarro (Chavarro J.) from the Harvard Institutes of Health is confident that the substance causes significant harm. Together with his colleagues, he examined 99 men who sought help with complaints of infertility. In semen tests from patients who consumed a lot of soy, sperm counts were found to be reduced. Normally, their concentration is 80-120 million in one ejaculate, but in Chavarro’s charges this figure was 41 million lower.
UK scientists are also seriously alarmed. Professor Sheena Lewis (Lewis S.) from Queen's University Belfast believes that genistein is especially dangerous for a male fetus and a newborn boy. Taking it can lead not only to a decrease in the number of sperm, but also to improper development of the sexual organ. But soy phytoestrogen easily passes from mother to child during pregnancy.
Also, due to the effect of the substance on the child’s hormonal system, the possibility of using soy preparations for juvenile osteoporosis is excluded.
Of interest is a study from the University of Stellenbosch (South Africa), in which 200 people of both sexes participated. The genistein diet reduced serum dehydroepiandrosterone sulfate (DHEAS) levels in both men and women. This is a steroid hormone, which is similar in structure to testosterone, and is easily converted into it in the body. (Swart A., Johannes I.).
Are cosmetics with phytoestrogens beneficial?
Many cosmetic brands produce products with phytoestrogens to care for aging skin. But can they really slow down the decline process? “If we are talking about a rejuvenating effect, then, alas, phytoestrogens are ineffective here,” says our expert. — Unlike steroid hormones, they are not absorbed through the skin and do not have a systemic effect. And since the substances contained in plant extracts themselves are inactive and the bulk of compounds with estrogen-like activity are formed in the intestines, you should not expect any pronounced effect from phytoestrogens applied to the skin. But in cosmetics for problem skin and products against baldness, they are useful as antioxidants and as inhibitors of the enzyme that stimulates sebum production.”
Find out also about the possibilities of hormone therapy during menopause.
Taking soy ingredients can lead to cancer
Most of all, scientists working on this topic are concerned with the question of whether genistein can accelerate tumor growth. This primarily concerns breast cancer. And today there are enough scientific publications to talk about the dangers of the substance - at least for some groups of the population. It is worth mentioning the work of University of Texas scientist Clinton Allred (Allred S.)
Together with his colleagues, he showed that a diet high in genistein stimulated the development of mammary gland tumors in ovariectomized mice. At the same time, the pathogenic effect was stronger in the group that received purified soy components - genistein and genestin . Animals fed soybean meal were less affected.
Such convincing evidence has put this substance at risk of being banned in Europe. The benefits and harms of soy are being carefully studied in Germany. The Senate Commission on Food Safety of the German Research Foundation (SKLM) recommends that at-risk groups avoid soy-based products. It includes people with iodine deficiency, hypothyroidism, and congenital thyroid dysfunction. They should also not be used by women who have breast cancer. Additionally, genistein should not be taken during pregnancy. Scientist from Hannover S. Heuser reports this in his work. (S. Hüser)
Chinese researchers have proven that OVCAR-5 cancer cells begin to grow when treated with genistein in vitro. This effect could potentially cause ovarian cancer. (Wang Y., Li W.)
Phytoestrogens: prospects for use
The article discusses the chemical structure, pharmacokinetics and mechanisms of action of phytoestrogens - natural plant food compounds that resemble human estrogens in chemical structure and biological activity. A review of works devoted to the influence of phytoestrogens on reproductive health, metabolism, the risks of developing various tumors, the state of the nervous, cardiovascular, skeletal and immune systems is presented. Research results suggest that the role of phytoestrogens in the prevention and treatment of many diseases will be reconsidered. Prospects for the use of phytoestrogens together with compounds that can bring maximum benefit have been noted. Hepiclim is given as an example of such a complex. The components included in its composition complement each other and potentiate each other's effects, providing a multi-purpose solution to problems with women's health.
Rice. 1. Chemical structure of estradiol and main phytoestrogens
Rice. 2. The mechanism of attachment of SARS-CoV-2 to the host cell in the presence of phytoestrogens and in their absence
Phytoestrogens are naturally occurring non-steroidal phenolic compounds from plants that, due to their molecular structure and size, resemble human estrogens, particularly estradiol (17-beta-estradiol). In plants, phytoestrogens function not as hormones, but as phytoalexins - low molecular weight compounds that are synthesized and accumulated during stress and attacks by microorganisms. These compounds have antibacterial, fungistatic, antiviral and antioxidant properties [1, 2].
Phytoestrogens have long been used as an alternative to hormone replacement therapy for menopausal syndrome [1–5]. At the same time, existing knowledge suggests that phytoestrogens may also influence a number of physiological and pathological processes associated with reproduction, infertility, bone remodeling, skin, cardiovascular, nervous, immune systems and metabolism. In addition, they may be useful for the prevention and treatment of symptoms of menopause, skin aging, osteoporosis, cancer, cardiovascular, neurodegenerative, immune and metabolic diseases [1–8]. However, there is still no consensus on the effectiveness of phytoestrogens and the conditions for which they are advisable to use [4, 5]. This work will analyze the possibilities of using various phytoestrogens in medicine.
Chemical structure of phytoestrogens and their sources
Phytoestrogens are divided into two main groups: flavonoids and non-flavonoids. Flavonoids include isoflavones, coumestans and prenylflavonoids, while non-flavonoids include lignans and resorcinol/stilbene derivatives. The structure of the main phytoestrogens is shown in Fig. 12]. Often several types of phytoestrogens can be found in one plant, and the same phytoestrogens can be found in different plant species [1, 3].
Isoflavones
Among the main isoflavones, it is necessary to highlight genistein, daidzein, glycitein, formononetin and biochanin A, contained in soybeans ( Glycine max
). Soy isoflavones, according to K. Setchell, are the most studied group of phytoestrogens: over the past 30 years, more than 15,000 articles have been published about them [5].
The amount of isoflavones in plant materials is affected by growing conditions and plant variety. Thus, their concentration increases sharply during times of stress (for example, low humidity, exposure to pathogenic microorganisms or plant diseases) and is largely dependent on environmental and climatic conditions: temperature, precipitation, harvest period or soil fertility. The final concentration of isoflavones is also determined by post-harvest processing [1].
The predominant forms of isoflavones in soybeans are genistein and daidzein, and to a lesser extent glycitein. They are conjugated with various sugars to form malonyl glucosides, acetyl glucosides and glycosides. Daidzein can be metabolized to equol, which has higher estrogenic potential than the parent substance, while genistein and glycitein can be converted to metabolites without estrogenic activity [3, 9].
Other legumes can also be sources of isoflavones. Specifically, red clover ( Trifolium pratense
) contains biochanin A and formononetin, which is converted to daidzein in the human gastrointestinal tract [1, 3].
If the feed of farm animals is rich in isoflavones, the latter are found in large quantities in milk (equol predominates) [1].
Koumestans
The main coumestans include coumestrol, 4′-methoxycoumestrol, repensol and trifoliol (see Fig. 1). Coumestrol is found in red clover, spinach, Brussels sprouts and legumes such as soybeans. High concentrations of coumestans are observed in peas, beans, alfalfa and clover sprouts.
Prenylflavonoids
Prenylflavonoids are found in hops and beer. The most powerful of them is 8-prenylnaringenin [1, 3].
Lignans
Lignans are representatives of non-flavonoid phytoestrogens with weak estrogenic activity. Lignan precursors are components of the plant cell wall and are found in oilseeds (flax seeds, sesame, soybeans, rapeseed), whole wheat grains, oats, rye cereals, various vegetables and fruits. Lignans (enterodiol and enterolactone) are formed from precursors by intestinal bacteria and act as the main source of phytoestrogens in the Western diet [1, 3, 8].
Resveratrol
Sometimes resveratrol is classified as a non-flavonoid phytoestrogens (stilbenes derivatives). It is present in grapes, berries, peanuts and certain teas. After oral administration, resveratrol is absorbed by enterocytes and undergoes conjugation with sulfate and glucuronate [3].
Pharmacokinetics of phytoestrogens
Phytoestrogens come from food. Conjugated forms of isoflavones are not absorbed in the intestine and are not bioavailable or biologically active.
The metabolism of soybean isoflavones in humans is well described in the literature. In the gastrointestinal tract, under the influence of bacterial beta-glucosidases, inactive isoflavones are hydrolyzed into bioactive aglycones. While some other aglycones are resistant to degradation and enter the colon, daidzein, genistein and glycitein are further transformed by intestinal flora. Daidzein can be metabolized to equol, a metabolite with potent estrogenic and antioxidant activity, as well as other, less active derivatives. Individuals differ in their ability to transform isoflavones into specific metabolites [1, 3, 5, 10]. Thus, there is no definitive explanation for why some people produce equol and others do not. The Japanese, Chinese and Koreans are known to do this better than non-Asians. This ability is explained by genetics, the composition of the intestinal microbiota and diet [3, 5, 9, 10]. Most likely, equol-producing gut microflora is absent or inactive because dietary manipulation with pre- and probiotics has failed to stimulate equol production. If the soy product has not been fermented, the proportion of biologically active unconjugated products will be relatively small. After circulating in the plasma, phytoestrogens are metabolized in the liver and excreted in the urine [1, 3].
The metabolism of isoflavones varies significantly between animal species and especially between humans and rodents, which must be taken into account when extrapolating data from experimental studies [1].
The bioavailability and pharmacokinetics of isoflavones depend on the texture of the food ingredients and the source or form of food consumed. Liquid food is absorbed more quickly and has a higher plasma concentration than solid food. Processing significantly affects isoflavone content and soy protein composition. Many soy foods in Asia have higher levels of bioavailable and bioactive glycones than their Western counterparts [5, 10].
Mechanisms of action of phytoestrogens
There are two types of mechanisms of action of phytoestrogens: those associated with modulation of the transcriptional activity of nuclear receptors and those not associated with nuclear receptor signaling [11].
Since phytoestrogens are similar in chemical structure to endogenous estradiol, they are able to bind to estrogen receptors (ER) alpha and beta [1, 3, 5]. RE-alpha stimulate cell proliferation, while RE-beta are responsible for cell apoptosis. RE-beta are located mainly in the bones, lungs, prostate gland, bladder, skin and brain, and RE-alpha are located mainly in the mammary gland, testicles, uterus, kidneys and pituitary gland. RE-alpha is physiologically more significant for women, while the role of RE-beta appears to be independent of gender [3].
Phytoestrogens are characterized by their affinity for RE and estrogenic activity. In general, phytoestrogens have lower estrogenic activity than estradiol [2]. However, the affinity of isoflavones for RE-beta is approximately five times higher than for RE-alpha, in contrast to estradiol, which has approximately the same affinity for both types of receptors. For genistein, the concentration required to activate RE-beta is much lower than for activation of RE-alpha [3, 5].
Based on in vitro
and
in vivo,
the rank order of phytoestrogenic activity was obtained: estradiol > genistein and equol > glycitein > daidzein > formononetin and biochanin A [1]. In relation to estrogen, phytoestrogens behave either as agonists (in case of estrogen deficiency), or in high concentrations as antagonists, which, by binding to RE, block the action of endogenous estrogen [1, 3]. A more modern approach classifies phytoestrogens into selective estrogen modulators and selective regulators of tissue estrogen action [12]. Isoflavones and lignans also function as inhibitors of cytochrome P450 aromatase, which catalyzes the conversion of androgens to estrogen [4].
Another target for phytoestrogens is peroxisome proliferator-activated receptors (PPARs) [11]. PPARs are nuclear receptors that are present in three isoforms: alpha, beta and gamma. Isoflavones (formononetin, biochanin A, genistein and daidzein) can activate PPAR-alpha, a master regulator of genes that are involved in beta-oxidation of fatty acids and vascular inflammation, as well as PPAR-beta, which can be activated by long-chain fatty acids and acts as a sensor fatty acids, regulating various genes involved in lipid metabolism. Several phytoestrogens, including genistein, daidzein, and resveratrol, can bind to PPAR-gamma, modulating its transcriptional activity. PPAR-gamma plays a central role in the regulation of adipogenesis, and activation of PPAR-gamma improves insulin sensitivity and glucose homeostasis [12].
Isoflavones are extremely powerful antioxidants, characterized by higher antioxidant activity than vitamins C or E, with S-equol having the highest antioxidant activity [5].
Phytoestrogens are able to activate serotonergic receptors, insulin-like growth factor 1 receptors, induce DNA methylation, influence tyrosine kinases, cyclic adenosine monophosphate, phosphatidylinositol 3-kinase/protein kinase B and mitogen-activated protein kinase, transcription. Thanks to this ability, phytoestrogens have antioxidant, antiproliferative, antimutagenic and antiangiogenic effects [3, 5, 11].
Phytoestrogens and reproductive health
Phytoestrogens have different effects on the reproductive process, which depends on many factors. Isoflavones may alter the timing of puberty and ovarian function in animals. Genistein is able to stimulate the production of progesterone in the ovaries, the production of estradiol and the production of cyclic adenosine monophosphate, the maturation of oocytes and the development of the zygote at the preimplantation stage [5]. According to several studies, isoflavones contained in infant formula affect the reproductive development of children [3].
The possibility of using phytoestrogens in perimenopause has been most studied. M. Chen et al. performed a meta-analysis of 15 high-quality randomized clinical trials. It turned out that taking phytoestrogens did not lead to a change in the Kupperman index compared to placebo, but significantly reduced the frequency of hot flashes without increasing the frequency of side effects. Prescribing phytoestrogens to relieve vasomotor symptoms in perimenopause appears to be appropriate since up to 74% of postmenopausal women, up to 70 years of age, experience hot flashes, which can negatively affect quality of life. The lack of significant reduction in the Kupperman index, which measures the severity of 11 menopausal symptoms, calls into question the usefulness of phytoestrogens for the relief of other menopausal symptoms [4].
Most authors find a beneficial effect of regular consumption of soy isoflavones on the health and quality of life of peri- and postmenopausal women [1, 3, 5, 9]. At the same time, isoflavones, unlike hormone replacement and menopausal therapy, do not increase the risk of developing breast and endometrial cancer, and also do not increase the risk of thrombosis [3]. However, the European Food Safety Authority concluded that there is insufficient evidence to establish a relationship between the reduction of vasomotor symptoms caused by menopause and the consumption of soy isoflavones [2, 7].
Lignans have not been as widely studied as isoflavones, but the current evidence suggests that their effectiveness in reducing vasomotor symptoms of menopause is no greater than that of placebo [3].
Phytoestrogens and cardiovascular diseases
The results of numerous studies indicate the normalization of lipid metabolism under the influence of isoflavones. Consumption of soy-derived phytoestrogens may reduce plasma low-density lipoprotein cholesterol and increase plasma high-density lipoprotein cholesterol, reduce plasma triglyceride concentrations, inhibit oxidized low-density lipoprotein, reduce blood pressure and C-reactive protein levels [1, 3, 5, 13].
The effect of isoflavones on endothelial function and vascular tone has been extensively studied. Genistein and equol have potent vasodilatory effects in both women and men, which are likely due to a nitric oxide-dependent mechanism. Soy isoflavones improve endothelial function in postmenopausal women, which should lead to lower blood pressure in the long term, according to two meta-analyses. Thus, after six months of taking isoflavones, postmenopausal women showed an increase in endothelial vasodilation and a decrease in the number of cell adhesion molecules. Isoflavones may increase renal blood flow, sodium excretion, and inhibit angiotensin-converting enzyme activity. Moreover, the hypotensive effect of isoflavones is more noticeable in patients with arterial hypertension than in normotensive patients [3, 5].
Phytoestrogens and obesity
Phytoestrogens can increase lean mass and decrease fat mass by inhibiting the adipocyte life cycle. The effects of phytoestrogens are primarily related to their ability to activate or suppress PPAR-gamma signaling in adipocytes. In experiments on rats, it was found that several phytoestrogens, including genistein and daidzein, in addition to inhibiting lipogenesis, induce lipolysis by inhibiting cyclic adenosine monophosphate in adipocytes, which slows down the accumulation of triglycerides and prevents their hypertrophy. Formononetin stimulates lipolysis and enhances the release of glycerol in adipocytes [5]. Administration of coumestrol to animals on a high-fat diet activated lipolysis in white adipose tissue depots and thus prevented obesity [3].
Research shows that phytoestrogens from soy and soy products help people lose weight. Long-term administration of isoflavones may reduce visceral adipose tissue and serum leptin concentrations. Fat loss can be explained by the ability of phytoestrogens to induce apoptosis of adipocytes, as well as suppress appetite [3].
Phytoestrogens can modulate the secretory profile of adipocytes, reducing the inflammation that occurs in obesity.
Genistein reduces the synthesis of pro-inflammatory interleukins (6) both in mice and in humans, the expression of leptin in fibroblasts. In addition, genistein-based supplements lead to the activation of interferon beta-1. Daidzein regulates pro-inflammatory gene expression by activating PPAR-alpha and PPAR-gamma, and by inhibiting the kinase pathway in adipocytes and macrophages.These effects include decreased expression of monocyte chemoattractant protein 1 and interleukin 6 and increased expression of adiponectin [12].
A meta-analysis of nine randomized clinical trials, all of which were conducted in postmenopausal women, demonstrated that soy phytoestrogens can help with weight loss [12]. A more recent meta-analysis, which included 23 randomized clinical trials and 1880 women, found a correlation between phytoestrogen supplementation and a decrease in waist circumference due to visceral fat [9]. On the contrary, in women with obesity-related disorders (diabetes mellitus, arterial hypertension, hyperlipidemia), body weight increased when taking phytoestrogen. According to a meta-analysis, daidzein may lead to adverse changes in body composition, as opposed to soy products or isoflavone mixtures. It was concluded that the effects of phytoestrogens on body weight are compound specific and depend on the underlying metabolic status of the individual [9, 12].
It is clear that under certain circumstances, phytoestrogen supplementation may help reduce body weight and visceral adipose tissue volume. Since phytoestrogens have a beneficial effect not only on the amount of adipose tissue, but also on its metabolism and secretory profile, they may be effective in the treatment of complications associated with visceral obesity [11].
Phytoestrogens and diabetes mellitus
According to D. Desmawati and D. Sulastri, phytoestrogens can reduce fasting blood sugar and insulin levels, the HOMA-IR insulin resistance index, but do not affect postprandial blood sugar levels [3]. The basis of these effects is probably the activation of PPAR receptors [2]. Consumption of soy protein with isoflavones and flaxseed has been shown to improve glucose control and reduce insulin resistance [5]. Genistein, daidzein, and glycitein have been found to increase insulin sensitivity and reduce plasma glucose and insulin levels in rodents with experimental type 2 diabetes mellitus and obesity. In addition, these isoflavones can stabilize beta cell function and delay the onset of diabetes in nonobese diabetic mice [12].
Lignan intake has been found to reduce fasting insulin and C-peptide levels in men. These results provide evidence that phytoestrogens can directly affect beta cell function and insulin secretion [8, 12].
A meta-analysis of ten randomized controlled trials (total of 794 non-Asian perimenopausal and postmenopausal women) did not find that soy isoflavone consumption improved insulin secretion and HOMA-IR [14].
An attempt to integrate and analyze data on the effects of phytoestrogens on glucose metabolism and diabetes mellitus was made in a systematic review and meta-analysis that included over 213,000 women [15]. It turned out that higher levels of phytoestrogen intake are associated with a reduced risk of developing type 2 diabetes in women. This analysis also noted that soy-derived isoflavones were associated with lower glucose concentrations, and isolated genistein was associated with lower insulin and HOMA-IR levels.
Phytoestrogens and cognitive function
Phytoestrogens can improve cognitive function by acting as neuroprotectors and antioxidants. They influence the nervous system through steroid receptors and 5-hydroxytryptamine receptors or by increasing serotonin reuptake [2, 3].
A meta-analysis of ten placebo-controlled randomized clinical trials of soy isoflavone supplementation (six to 30 months) showed beneficial effects on cognitive function and visual memory in postmenopausal women (n = 1024) [16].
Another review included seven observational studies, and only three found beneficial effects of isoflavones on cognitive processes [5].
In another study, of the 12 randomized clinical trials reviewed, six found positive results of isoflavone supplementation on cognitive function. It was concluded that treatment outcome depends on many factors: age, gender, ethnicity and hormonal status, as well as the duration of phytoestrogens consumption and the tests used to assess cognitive function [2].
Phytoestrogens and bone health
The beneficial effect of phytoestrogens on bone mineral density is achieved through the synthesis of osteoblasts and a decrease in bone resorption, but is observed with long-term consumption of phytoestrogens, for a minimum of six months [1, 3, 5]. It is known that consumption of soy milk, rich in isoflavones, for two years led to an increase in bone mineral density in older women by 2.4% [3].
However, a meta-analysis of randomized clinical trials in humans revealed a weak correlation between increasing the consumption of soy isoflavones and increasing bone mineral density [3]. The European Food Safety Authority concluded that the available evidence is insufficient to establish a relationship between the maintenance of bone mineral density and the consumption of soy isoflavones [2]. These discrepancies may be due to differences in exposure time to isoflavones, the amount of isoflavones in food, and differences between specific dietary supplements, foods, and pure compounds [1, 17].
Phytoestrogens and carcinogenesis
Soy isoflavones can be used as an alternative therapy for a wide range of hormonal disorders, including several types of cancer, most notably breast cancer [1, 3]. Phytoestrogens can reduce the risk of tumor development by inhibiting the activity of the aromatase enzyme and the expression of the CYP19 gene in human tissues [18].
To date, five independent prospective epidemiological studies have been conducted (two in the USA and three in China) lasting three to seven years. In total, they observed more than 11,000 patients who survived treatment for breast cancer. It was concluded that soy consumption is associated with a statistically significant reduction in breast cancer recurrence and mortality [5]. In addition, consumption of soy foods/isoflavones appears to increase the effectiveness of tamoxifen and aromatase inhibitor treatment. The American Cancer Society and the American Institute of Cancer Research endorsed the findings that consumption of soy foods is safe and improves prognosis for breast cancer survivors [1].
A meta-analysis of 40 randomized controlled trials, 11 uncontrolled studies, and 80 observational studies also demonstrated that soy consumption likely reduces the risk of breast cancer incidence, recurrence, and mortality. It is important to note that this protective effect may be due to early soy consumption [2].
Various studies have shown that the use of isoflavones can reduce the risk of developing lung, stomach, thyroid and prostate cancer [3, 5]. Women who prefer foods rich in isoflavones or soy are less likely to develop endometrial and ovarian cancer [3].
A reduced risk of breast cancer was also found for lignan at high doses in postmenopausal women [2].
Phytoestrogens and the immune system
The level of estrogen in the blood largely determines the immune response. The importance of proper estrogen concentrations is supported by evidence that the severity of COVID-19 depends on estrogen status [19]. It is known that phytoestrogens have immunomodulatory activity both due to the ability to inhibit intracellular signaling pathways associated with immune responses and due to their effect on the microbiota [3, 20].
Phytoestrogens (daidzein, genistein, formononetin and biochanin A) have been shown to interact with cell surface heat shock protein A5 and interfere with the entry of SARS-CoV-2 into cells (Fig. 2) [21]. This suggested that phytoestrogens could be successful anti-COVID-19 agents for people at high risk: the elderly, cancer patients and medical personnel in contact with coronavirus infected people [21].
Genistein can inhibit the allergic inflammatory response, increase cytokine production from T cells, and enhance cytotoxic responses mediated by natural killer cells and cytotoxic T cells [3].
Prospects for the use of phytoestrogens
Despite the many benefits of phytoestrogens, the effect of isoflavones can be enhanced by using them together with other substances that can provide maximum benefit. This makes it advisable to develop complex products such as Hepiclim. In addition to soy isoflavones, its composition includes magnesium citrate, dry extract of lemon balm ( Melissa officinalis
), vitamins C, B6 and B1 [22]. All these components complement each other and potentiate each other’s effects, providing a multi-purpose solution to women’s health problems.
Melissa contains phenolic components, including flavonoids with a pronounced antioxidant effect. Its extract can have anti-anxiety, antidepressant, neuroprotective effects, improve mood, memory and cognitive functions. There is also evidence of the anti-carcinogenic properties of lemon balm. An additional benefit for patients with metabolic syndrome during perimenopause is the effect on the cardiovascular system (cardioprotective, antiarrhythmic), normalization of glucose and lipid metabolism. Melissa is used in the treatment of sleep disorders, nervousness, anxiety, and gastrointestinal diseases during menopause [23, 24].
Magnesium plays an important role in maintaining normal function of the muscular and nervous systems, normal heart rhythm, and potentiates the effect of antihypertensive drugs [25].
Vitamins increase the body's adaptive capabilities, participate in the synthesis and metabolism of hormones and nervous system mediators.
Taking Hepiclim reduces the frequency and severity of vegetative-vascular manifestations, helps eliminate psycho-emotional disorders, and normalizes sleep in menopausal patients [22]. Considering the properties of soy isoflavones, there is a high probability that Hepiclim will be effective in the complex treatment of metabolic syndrome, obesity, and diabetes. The combination of isoflavones and vitamins provides a beneficial effect of Hepiclim on the immune status and the course of the inflammatory process.
Conclusion
Phytoestrogens are a group of compounds that can provide significant benefits in various diseases of the reproductive system, especially during menopause. In addition, phytoestrogens may be useful in the prevention and treatment of certain types of cancer, osteoporosis, cardiovascular, neurodegenerative, immune and metabolic diseases.
Conflicting data from clinical studies and meta-analyses is likely due to the heterogeneity of the trials: they are often conducted with different phytoestrogens at different doses. A certain contribution is made by differences in the intestinal microbiota, which is involved in the formation of active metabolites, polymorphism of genes involved in the metabolism of phytoestrogens, and endogenous estrogen levels.
The effectiveness of phytoestrogens can be increased by using complex preparations that contain substances that have a synergistic effect.
Genistein and the thyroid gland: menopausal women are at risk
The effect of genistein, like other soy isoflavones, on the thyroid gland cannot exactly be called positive.
This is stated in a study by Japanese authors (Kimura S., Suwa J.). These scientists say that this substance is especially dangerous for people with iodine deficiency. Rats fed low-fat soy without iodine developed hyperplastic goiter, and malignant tumors were found in the gland. When iodine was added to the diet, the condition of the thyroid gland improved - it returned to its normal size. The work of Daniel Doerge and Daniel Sheehan is also of interest. (Doerge D., Sheehan D.). In it, scientists indicate that genistein reduces the production of peroxidase, which is necessary for the synthesis of thyroid hormones - triiodothyronine (T3) and thyroxine (T4). According to their data, peroxidase activity under the influence of soy decreased by 80%. All this should be kept in mind when choosing a drug for osteoporosis, especially considering the vulnerability of the thyroid gland and mammary glands in menopausal women.
Soy and GMOs are almost synonymous
There is one more aspect that cannot be ignored when talking about genistein. Today, 90% of all soybeans grown in the world are genetically modified. Although supporters of GMO products claim that they are safe and have passed the necessary tests, there are plenty of opponents. And they are also based on research. The main argument of critics of transgenic food is that the consequences it will have over time are unknown.
Whether to consume soybean products, including dietary supplements with genistein, or not, everyone is free to decide for themselves. But it would be a mistake to ignore the facts confirming its undesirable effect.
