The Beneficial and Adverse Effects of Phytoestrogens
Department of Surgical Research and Techniques, The Heart and Vascular Center, Semmelweis University, Faculty of Medicine, Budapest 1089, Nagyvárad square 4., Hungary
Eötvös Loránd Bilingual Primary School, Százhalombatta 2440, Liszt Ferenc walk 2., Hungary
Academic Editor: James D. Adams
Special Issue: Advantages of Traditional Healing and Use of Plant Medicines
Received: May 19, 2022 | Accepted: July 24, 2022 | Published: August 08, 2022
OBM Integrative and Complementary Medicine 2022, Volume 7, Issue 3, doi:10.21926/obm.icm.2203034
Recommended citation: Blázovics A, Csorba B, Ferencz A. The Beneficial and Adverse Effects of Phytoestrogens. OBM Integrative and Complementary Medicine 2022; 7(3): 034; doi:10.21926/obm.icm.2203034.
© 2022 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
In the 1930s, sheep that consumed large amounts of clover and alfalfa were found to be infertile in Australia. The cause was later associated with the estrogenic effects of isoflavonoids .
Isoflavonoids cause endocrine disruption, i.e., they alter the functions of the endocrine system. They bind to hormone receptors in the body and influence their function, production, hormone synthesis, transport, and breakdown. These effects are also observed in the offspring .
Isoflavonoids are a subclass of polyphenolic flavonoids. They are natural compounds with 3-phenylchroman structures that are derived directly from benzo-γ-pyrone. Isoflavonoids are plant-based secondary metabolites, which mainly belong to the Papilionoideae subfamily of Fabaceae or Leguminosae.
In this review, we presented the pharmacological effects of phytoestrogens, including the bioavailability of isoflavonoids, by describing some important medicinal and food plants.
2. Materials and Methods
Scientific publications were studied via the intranet available at Semmelweis University. We reviewed the Web of Science multidisciplinary bibliographic database provided by Clarivate Analytics (previously: Thomson Reuters), PubMed free, journal indexing bibliographic medical database, and Scopus multidisciplinary bibliographic database provided by Elsevier.
3. Structure and Grouping of Estrogens and Phytoestrogens
Estrogens (17β-estradiol, estrone, and estriol) are sterane compounds, where the third carbon atom of the aromatic ring A has a hydroxyl group, and the carbon atom of the ring D has a hydroxyl or oxo group. These sterane compounds are found in animals. Estrogens and isoflavonoids are structurally very similar (Figure 1).
Figure 1 The structural formula of estrogens.
The biological activity of estrone, estriol, and 17 β-estradiol is approximately 1:7:100. The compound 17β-estradiol is an endogenous major steroid hormone and the primary female sex hormone. It also plays a key role in the etiology of breast, prostate, endometrial, and ovarian cancers .
Animal-derived estrogens and plant-derived phytoestrogens can bind to the same estrogen receptors as they have similar molecular structures .
Phytoestrogenic compounds include flavonoids, isoflavonoids, lignans, coumestans, prenylflavonoids, and stilbenoids, which belong mainly to the Leguminosae family and other families as well .
Within the family of flavonoids, some flavones, flavonols, and flavanones have estrogenic properties.
Flavonoids are synthesized by the phenylpropanoid metabolic pathway from phenylalanine to form p-coumaroyl-CoA (4-coumarate-CoA) due to the activity of several enzymes, including phenylalanine ammonia-lyase, cinnamate 4-hydroxylase, and 4-coumarate CoA ligase.
Next, it binds to malonyl-CoA due to the activity of chalcone synthase and forms the backbone of the flavonoid molecule. These compounds are known as chalcones and contain two phenyl rings. The chalcone isomerase enzyme closes the ring, which leads to the formation of a three-ring structure.
The metabolic pathway is regulated by the activity of enzymes. For example, flavonols, flavan 3-ols, and other polyphenols (e.g., isoflavonoids) are formed from naringenin due to the activity of isoflavone synthase, whereas genistein, daidzein, and glycitein are formed from liquiritigenin due to the activity of isoflavone synthase.
Flavonoids, especially isoflavonoids, show high structural variability, and the molecular structure of thousands of their representatives is now known. The variation occurs due to the degree of oxidation and substitution. These compounds highly differ in the number and position of the phenolic hydroxyl groups. The antioxidant effect of flavonoids depends on the location of the functional groups in the molecule; however, these substitution sites are also responsible for frequent toxicity. Thus, redox transitions also influence the reactions .
Hundreds of compounds of lignans composed of phenylpropane units occur in nearly 70 plant families. They accumulate in several plant parts (e.g., fruits, seeds, and roots). The metabolites of enterodiol, secoisolariciresinol, enterolactone and matairesinol-type lignans have estrogenic effects. They are enriched in significant amounts in flaxseed, sesame seeds, and wheat but are also found in beans and pumpkins. Besides containing daidzin, genistin, daidzein, genistein, formononetin, and biochanin A, green coffee also contains three lignans, secoisolariciresinol, matairesinol, and lariciresinol. Flavonolignan (silychristine, silybinine, and isosilybinin) is found in the milk thistle fruit .
In general, the bioavailability of plant-originated polyphenols is determined by their chemical structure. The lignans that have low intestinal absorption are metabolized quickly. Lignans are demethylated and deoxygenated in the gastrointestinal tract by the gut microbiota.
If 17β-estradiol levels are normal in the body, lignans act as estrogen antagonists. However, if the 17β-estradiol levels are low, lignans can exhibit a weak estrogenic effect .
Nearly 300 plants contain isoflavonoids, many of which have estrogenic effects. Their most important members occur in legumes belonging to the Fabaceae family. Soy, Glycine max (L.) Merril is extremely nutritious.
More than 1,000 types of isoflavonoids have been isolated.
Coumestans are derivatives of isoflavonoids and are common in legumes. Their concentration is the highest in alfalfa (Medicago sativa), red clover (Trifolium pratense), and soybean germ (Glycine max).
The main source of resveratrol is red grapes. Resveratrol treatment can reduce the risk of menopausal cardiovascular diseases and decrease the progression of osteoporosis .
Mention should also be made of the Janus-faced property of resveratrol (antioxidant, prooxidant, and affects transmethylation), as the compound is highly advertised.
Resveratrol can also bind to nuclear estrogen receptors and modify its genomic activity. It also interacts with membrane estrogen receptors and affects non-genomic estrogen activity. The compound interferes with steroidogenesis and inhibits the steroid biosynthesis pathway. Resveratrol inhibits the hepatic and intestinal metabolism of estrogen. Chronic exposure is dangerous because it might cause endocrine disorders .
Resveratrol weakly stimulates estrogen receptors. Phytoestrogenic resveratrol might be used for treating hormonal disorders associated with polycystic ovary syndrome (PCOS). Female Sprague-Dawley (SD) rats treated orally with letrozole showed normal ovarian morphology after treatment with resveratrol .
Some studies have found that resveratrol can bind to methyl groups and affect transmethylation; therefore, its role is not favorable .
The transmethylation capacity of cancer patients is poor. Tumor anemia is strongly affected by globin methylation. Uncontrollable anemia can be alleviated by methyl donor compounds .
Phytoestrogens have been studied extensively in the last decade .
Figure 2 Phytoestrogenic compounds.
Mammalian lignans, such as enterodiol and enterolactone, are diphenolic compounds. They are formed from plant precursors due to the actions of bacterial enzymes in the colon. Mammalian lignanes can help to prevent cancer [18,19,20].
Phytoestrogens are also found in algae, cyanobacteria, and fungi .
Molds belonging to the genus Fusarium also contain estrogenic compounds, but they are toxic resorcilic acid lactones (Figure 3).
Figure 3 The structural formula of an estrogenic compound of Fusarium.
Resorcylic acid lactones (RALs) are potent irreversible inhibitors of the HSP90 chaperone protein or MEK and TAK kinases, which are involved in several signaling cascades. These compounds inhibit the VGFR (vascular endothelial growth factor receptor protein). RALs are highly effective chemotherapeutic agents and might be suitable for treating inflammation. (Effects of RALs: radicicol and pochonin D are HSP90 inhibitors, hypothemycin is a MAP kinase inhibitor, LL-783, 277 is a MEK inhibitor, pochonin C is an HSV inhibitor, and LL-Z1640–2 is a TAK –1 inhibitor) .
4. Bioavailability of Isoflavonoids
Phytoestrogens have a beneficial effect on endothelial cells, the smooth muscle cells of the vessel wall, and the extracellular matrix. Isoflavonoids can help to reduce the risk of cardiovascular diseases and type 2 diabetes mellitus due to their scavenger, lipid, and anti-inflammatory properties .
The glycosides of isoflavonoids are poorly absorbed in the intestinal tract due to their molecular weight and hydrophilic properties. Isoflavonoids can be O and C glycosides. In the intestinal tract, they are converted by esterases and/or β-glycosidase enzymes to aglycones, which are absorbed more efficiently (Figure 4).
After adsorption via the intestinal epithelium, they are incorporated into kilomicrons. Kilomicron remnants enter the liver, where isoflavonoids are metabolized mainly by glucuronidation and to a lesser extent by sulfation. After metabolism, they are excreted with bile, where the metabolites become a part of enterohepatic circulation.
The enzymes of intestinal bacteria cleave glucuronic acid, and isoflavonoids are reabsorbed into the systemic circulation. Most of them are excreted in the feces, but 10–30% are present in the urine.
Figure 4 Biotransformation of iso(flavonoids).
In the gastrointestinal tract, (iso)flavonoid glycosides are hydrolyzed into bioactive aglycones at the brush border membrane due to the action of bacterial β-glucosidases. After being absorbed, (iso)flavonoids are metabolized to β-glucuronides and sulfate esters in the intestinal mucosa cells .
The isoflavonoid type daidzein, genistein, and several structurally related compounds can inhibit 17β-estradiol-induced hormone-dependent tumors. Isoflavones might influence the glucuronidation of 17β-estradiol in human hepatic microsomes [25,26].
Phytoestrogenic flavones, flavonols, flavanones, and isoflavonoids are the most effective anti-inflammatory flavonoid derivatives. These compounds are effective in arachidonic acid-induced inflammation. Some of the compounds include naringenin, chrysin, apigenin, galangin, quercetin, kaempferol, and biochanin A.
They mainly attack phospholipase A2, cyclooxygenase-2 (COX2), lipoxygenase (LOX), and NO synthase. They also affect signaling pathways .
The formation of prostaglandins and leukotrienes is initiated by free radicals. Free radicals also increase the activity of phospholipase A2. Both LTB4 (Leukotriene B4) and IL-2 (interleukin-2) enhance the activity of NK (natural killer) cells .
Extracts containing the phytoestrogen baicalein of Scutellaria baicalensis and catechin of Acacia catechu are effective inhibitors of COX-1, COX-2 (Cyclooxygenase-1, 2), and 5-LOX (5-lipoxygenase); thus, they can reduce the synthesis of inflammatory eicosanoids and edema in an animal model of inflammation (in vivo) .
Formulations made from them (e.g., Limbrel/USA; Ato Formula/South Korea) have been used successfully for treating osteoarthritis .
The effect of soy isoflavonoids has been studied in vitro and on different experimental inflammatory models. The results showed that these compounds have anti-inflammatory activity as structural analogs of 17 β-estradiol.
The effect of genistein was investigated on cell-mediated inflammatory responses in vivo and also on mouse models of oxazolone-induced delayed-type hypersensitivity reaction (dependent on T cells/macrophages) and olive oil-induced inflammatory response (granulocyte-dependent but T cell/macrophage independent). Soy isoflavone reduced inflammation and inhibited the activity of granulocytes, monocytes, and lymphocytes. Thus, genistein was found to suppress cell-mediated immune responses .
Isoflavonoids can interact with M cells, dendritic cells, mast cells, and other cells in the gut to influence the immune system. Several immune cells are found in the lymphoid tissue of the intestinal mucosa and the GALT (gut-associated lymphoid tissue). The highly specialized M cells are located here, while T and B lymphocytes and macrophages are present in their pockets. These cells carry the antigens to the lymphoid tissue. Peyer’s patches in the ileum are secondary lymphatic follicles in which antigens activate B cells and convert them to IgA-producing plasma cells [31,32,33].
Figure 5 A schematic representation of the gastrointestinal mucosa.
Inflammatory cytokines include IFN-α, β, γ, IL-1α, β, IL-6, IL-10, IL-12, TNF-α, β, MIF, and chemokines. They are mainly synthesized by mononuclear phagocytes, γ/δ T cells, granulocytes, mast cells, dendritic cells, fibroblasts, and endothelial cells. These cytokines cause inflammatory responses, initiate the activation of specific immune cells, and regulate their differentiation .
Dendritic cells facilitate communication between the innate and adaptive immune systems. They present antigens to T cells. Their Toll-like receptors recognize pathogens and dendritic cells phagocytose them. During maturation, these fragments are presented on their surface using the major histocompatibility complex (MHC). After maturation, several molecules such as CD40, CD80, CD86, CD58, and MHC are upregulated on the cell surface significantly increasing their ability to activate T cells. The activated dendritic cells release cytokines, prostaglandins, and NO and promote inflammation by directing cellular migration. Dendritic cells can activate memory and naive T cells. The dendritic cells, M cells, and mast cells in the gut can come into contact with the intestinal lumen, and thus, the isoflavonoids in food have a direct effect on these cells.
Genistein, daidzein, equol, biochanin A, and formononetin act in different modes on the maturation and activation of dendritic cells. Daidzein can significantly inhibit the expression of CD40, CD80, and CD86 (costimulatory molecule) maturation-associated cell surface markers and major histocompatibility complex class II (I-Ab) in a dose-dependent manner. Daidzein can suppress pro-inflammatory cytokines but does not affect IL-10 and IL-1β expression.
Daidzein, genistein, and equol can inhibit lipopolysaccharide (LPS)-stimulated dendritic cells with the downregulation of the expression of CD86.
These molecules have immunosuppressive effects and can suppress the maturation of dendritic cells and, consequently, the production of pro-inflammatory cytokines .
Genistein significantly decreased IL-6 and IL-1 beta production during PMA/A23187 (Phorbol myristate acetate/Ca2+ ionophore A23187)-induced mast cell activation .
Apigenin, quercetin, genistein, and (+/-) equol inhibit rat and human 11β-HSD1 and 11β-HSD2 enzymes in a concentration-dependent manner and thus, have antidiabetic activity. The potency of the effect follows the order: apigenin > quercetin > genistein >> (+/-) equol on human 11β-HSD1 reductase. These compounds bind to the steroid-binding site of human 11β-HSD1 and function as non-competitive inhibitors of 11β-HSD1 when steroid substrates are used. Apigenin is a selective inhibitor of two human 11β-HSD isoforms. Genistein can also inhibit rat 11β-HSD1 reductase, while the other three chemicals have no effects on the enzyme activity at low concentrations .
The bi-functional 11β-hydroxysteroid dehydrogenase (11β-HSD) isozyme 11β-HSD1 converts cortisone to the active hormone cortisol, and 11β-HSD2 converts cortisol to inactive cortisone. Thus, they play an important role in diabetes mellitus .
The antiviral effects of daidzein, genistein, glycitein, and coumestrol were investigated on the replication of the herpes simplex virus (HSV), and genistein and coumestrol were found to inhibit HSV-1 (acyclovir-sensitive and acyclovir-resistant KOS and 29R strains) and HSV-2 (333 strain) replication at non-cytotoxic concentrations, but daidzein and glycitein showed no antiviral effects. Coumestrol acted in the early stages of viral infection. Genistein and coumestrol strongly inhibited HSV-1 (29R strain) and HSV-2 replication, rather than the replication of HSV-1 (KOS strain). Coumestrol affected the early stages of viral infection, and both genistein and coumestrol reduced HSV-1 protein expression and the spread of HSV-2 between cells . Effective antiviral drugs for COVID-19, caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus), are not available yet. Thus, isoflavonoids were examined in an in silico study to determine the effectiveness of these drugs on the ACE2 (angiotensin-converting enzyme 2) cell-entry receptor and on Mpro, the main protease that is essential for viral replication. The researchers investigated whether isoflavonoids could demonstrate antiviral effects on SARS-CoV-2. Molecular docking studies have been performed on 59 isoflavonoids .
Drug-likeness properties were calculated using Lipinski’s rule. Almost all compounds in the study followed Lipinski’s five rules.
In ADMET Studies (absorption, distribution, metabolism, excretion, and toxicity) on the plasma protein binding model, the results showed that the compounds genistein and daidzein could bind to plasma protein more than 95%, while glycitein showed a binding pattern of more than 90% (The target protein crystal structures were obtained from the RCSB Protein Data Bank by the authors.)
The isoflavonoids were investigated through molecular docking studies, and their binding capabilities against ACE-2 and Mpro were determined.
All isoflavonoids were found to bind strongly to the hACE-2 receptor. The binding of isoflavone derivatives daidzein, genistein, and glycitein to the hACE-2 receptor was relatively weaker than the binding of some isoflavone derivatives, but it was stronger than the binding of the pterocarpan derivatives to the hACE-2 receptor. All tested isoflavones could bind to the active site of the coronavirus Mpro (PDB:6LU7) with one or more hydrogen bonds, as determined by molecular docking studies .
5. Properties of Phytoestrogens and Their Role in Signal Transduction
Depending on the concentration of the free radicals released from the antioxidant control contribute to the disruption of vital cell functions, thereby inducing apoptotic or necrotic cell death. Free radicals rapidly activate extracellular signaling-regulated kinases (ERK1/2), c-Jun N-terminal kinases (JNK/SAPK), and p38 mitogen-activated protein kinases (MAPK). They also induce the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and Akt (serine/threonine protein kinase) signaling pathways. Thus, free radicals induce apoptosis and proliferation of cells [42,43].
Recent studies on molecular biology have investigated the role of many plant-active substances in signal transduction. Isoflavonoids have radical scavenging/antioxidant properties, which might help to inhibit signaling pathways. However, these properties do not enhance isoflavonoid function as hormones .
Phytoestrogens partly act by binding to estrogen receptors and partly by influencing signaling molecules that initiate signaling pathways. Their receptor affinity is lower than that of estrogens. Phytoestrogens regulate the function of cells by affecting signal transduction pathways.
In animals, genistein, daidzein, and glycitein inhibit carcinogenesis by regulating the cell cycle and apoptosis.
Soy isoflavones, genistein, daidzein, and glycitein have pleiotropic effects on cancer cells. They target multiple cellular signaling pathways, including NF-κB, Akt, MAPK, Wnt (cysteine-rich glycoproteins with highly conserved cell signaling systems), and p53 (tumor suppressor protein) .
Most studies related to isoflavones have been performed on genistein. Genistein antagonizes estrogen-mediated and androgen-mediated signal pathways. It has antiproliferative or pro-apoptotic effects and inhibits the growth of cancer cells by inhibiting the PTK (protein-tyrosine kinase), protooncogene HER-2, topoisomerase I, and II, 5α-reductase, protein histidine kinase, as well as, the NF-κB and Akt signaling pathways .
Genistein acts as a programmed cell death inducer by downregulating the expression of the Bcl-2 protein (B-cell lymphoma 2), regulating cell death (apoptosis), upregulating the expression of Bax (a subfamily of Bcl2-related proteins), and activating caspase-3 (cysteine-aspartic acid protease), which is a lysosomal enzyme involved in the apoptotic pathway that enhances apoptosis . Genistein exhibits anti-mutagenic and anti-metastatic effects. It inhibits signal transduction pathways and promotes tumor reduction by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells .
Genistein inhibits the activation of the members of the STAT (signal transducer and activator of transcription) protein family, including STAT-3 and STAT-5, IGF-1R (insulin-like growth factor 1 receptor), Ape-1/Ref1 (apurinic/apyrimidinic endonuclease 1/redox effector factor 1), Wnt (cysteine-rich glycoproteins), CREB (cAMP response element-binding protein), and HIF-1α (hypoxia-inducible factor 1-α). It also stimulates the Nrf1, Nrf2 (nuclear factor erythroid 2-related factor-1, nuclear factor erythroid 2–related factor 2), and GADD 153 (endoplasmic reticulum (ER) stress-induced apoptotic pathway) transcription factors. This stimulates the p53 tumor suppressor gene.
Genistein influences the cell cycle (cell cycle progression from G2 to M phase) by downregulating cyclin B1 (involved in mitosis) and cyclin D1 (important regulator of cell cycle progression) regulatory proteins, decreasing the Wee-1 (serine/threonine-protein kinase) nuclear kinase, CDK-1 (cyclin-dependent kinase 1) kinase, and increasing the activity of p21WAF1, p27 KIP1, and p16 INK4a cyclin-dependent kinase inhibitors [50,51,52,53,54].
Biochanin A, genistein, daidzein, glycitein, and formononetin have beneficial effects on altered carbohydrate and lipid metabolism and also on the severe disease-induced complications (cardiovascular diseases, nephropathy, neuropathy, and retinopathy) in type 2 diabetes mellitus.
The PPARs (α and γ) (peroxisome proliferator-activated receptors) are activated by these soya isoflavonoids. These nuclear receptors strongly influence the regulation of insulin sensitivity and glucose homeostasis [39,55].
Genistein inhibits COX2 enzyme activity by inhibiting the prostaglandin biosynthesis cascade and moderates immune reactions. It can inhibit MMP-9, MMP-2 (matrix metallopeptidases), p38 MAPK, ERK-1/2 mitogen-activated protein kinases, RANK/RANK-L (receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin (OPG) system, and PTEN (phosphatase and tensin homolog) unique tumor suppressor gene .
Genistein can increase the level of GPx (glutathione peroxidase) antioxidant enzyme, kangai-1 (transmembrane glycoprotein that functions as a metastasis suppressor protein), and endoglin (type 1 membrane glycoproteins) on the cell surface; thus, inhibiting angiogenesis, tumor growth, survival, and metastasis of cancer. Due to its antioxidant character, it can also inhibit angiogenesis .
Genistein has apoptotic effects on prostate cancer, brain tumor, lung cancer, bladder cancer, ras-dependent bladder cancer, neuroblastoma, leukemia ovarian cancer, gastrointestinal, and colon cancer cell lines, among others. Cytotoxic and apoptotic effects of genistein have been demonstrated on estrogen-dependent/independent breast cancer cell lines .
Isoflavonoids of cowpea have also been investigated. The isoflavonoids and vitamin D of cowpea daidzein and genistein together activate the BMP-2/Smad (bone morphogenetic protein-2 growth factor/Smad signal transduction pathways) signaling pathway of osteoblasts in osteogenesis and promote further proliferation and differentiation of osteoblasts. These results showed that isoflavones (daidzein and genistein) isolated from cowpea can be used in the treatment of bone disorders [57,58].
Genistein can inhibit angiogenesis in several ways, for example, by modifying signaling pathways and influencing gene expression. At concentrations of 5 to 50 µM, it can inhibit the growth of human umbilical vein endothelial cells (HUVECs) and significantly inhibit the expression of VEGF (vascular endothelial growth factor), which is a regulator of angiogenesis.
Genistein might exhibit anti-cancer effects by inhibiting the VEGF-mediated signaling pathway between tumor cells and endothelial cells.
It might also inhibit the activation of the hypoxia-induced factor-1 (HIF-1) protein. Additionally, it inhibits the expression of the VEGF gene in this pathway. Other important proteins involved in angiogenesis are also inhibited in genistein-treated cells, such as platelet-derived growth factor (PDGF) and urokinase plasminogen activator (uPa) .
6. Advantages and Disadvantages of Hormone Replacement Therapy
Although menopause has been investigated extensively, studies on it before the 19th century were rarely conducted.
The term menopause is attributed to the French physician Charles-Pierre-Louis de Gardanne, who coined it from the words man and pause (break) in 1821.
In Germany, attempts were made in the 1800s to reduce women’s sexual complaints by treating the symptoms of menopause by administering the ovarian tissues of cows via injection and oral therapy, which led to significant improvements.
Papanicolaou (1883–1962) first described the role of estrogen (estrogen and the role of the hypothalamic-pituitary-adrenal (HPA) axis in guinea pigs), and this laid the foundation for hormone replacement therapy .
The treatment of menopause has been in the interest of doctors since the 1930s .
Estrogens have a significant effect on the reproductive and multiple organ systems of women and men; thus, they affect many physiological functions. Early studies on sex hormones were performed by the biologist and physiologist Edgar Allen, who studied the effect of follicular fluids on uterine weight, vaginal maturation, and sexual susceptibility in 1923. The biochemist Edward A. Doisy in the United States (professor of biochemistry and later director at St. Louis University School of Medicine in 1924) and the German chemist Adolph F.J. Butenandt (Institute of Chemistry at the University of Göttingen) also conducted their research at the same time, independently. Allen gave follicular fluid to Doisy, who extracted and crystallized estrone. He reported his results at the 13th International Physiological Congress in Boston in 1929. Doisy patented his process in 1934. Later, Doisy isolated estriol and estradiol. Butenandt purified and crystallized estrone and published the results together with Leopold Ruzicka before the manuscript of Doisy was published. Thus, they received the Nobel Prize (1939) for their research and the crystallization of testosterone. Butenandt isolated progesterone in 1934, estradiol in 1936 in collaboration with his colleagues, and testosterone in 1939 .
Hormone replacement therapy was started in the 1950s. Estrogen was initially purified from the urine of pregnant horses and later was produced synthetically. Initially, it was distributed mainly among popular actresses employed in the American and Western European film industries, and then, its usage gradually spread in civil society. Estrogen treatment can effectively alleviate the unpleasant physical and mental symptoms of menopause.
The Menopause Rating Scale (MRS) summarizes all the symptoms that occur frequently and require medical treatment in severe cases.
The menopause rating scale:
- Psychological symptoms: 0–16 points (four symptoms: depression, irritability, anxiousness, and exhaustion)
- Somato-vegetative symptoms: 0–16 points (four symptoms: sweating/flushing, heart problems, sleep disturbances, and joint and muscle problems)
- Urogenital symptoms: 0–12 points (three symptoms: sexual problems, urinary complaints, and vaginal dryness) .
During hormone replacement therapy, estrogens increase salt and water retention, thereby forming edema, increasing breast tension, and increasing the synthesis of blood clotting factors and fibrinogen, which can cause thromboembolism and stroke. Breast and endometrial cancers and an increase in tumor size commonly occur after estrogen therapy. All these problems might be associated with discomfort, hypertension, headache, and depression.
Because estrogens have a proliferative effect on the endometrium, after 1975, estrogen was used along with progesterone (the main metabolic hormone) or progestin to prevent the development of endometrial tumors.
Combined hormone replacement therapy, however, was not safe. The incidence of breast cancer decreased slightly, and progesterone prevented the development of uterine tumors, but vaginal bleeding, bloating, cholelithiasis, breast tenderness, venous thromboembolism, stroke, and depression persisted [66,67,68].
In 2002, JAMA reported an increase in the risk of thrombosis and stroke as a result of hormone replacement therapy .
Despite significant advancements in hormone replacement therapy (topical, systemic, and transdermal), most women are skeptical about HRT and even reject medical advice in critical situations, such as in scenarios of high risk of osteoporosis and cardiovascular diseases. In 2018, only 1% of women in Hungary received hormone replacement, although due to unwanted age-related changes, considerably more women would need it under adequate medical control . Women often use natural active ingredients to avoid side effects .
7. Hormone Replacement and Phytoestrogens
In the Asian population, 80% of the people can produce S-equol from the main isoflavone of soy, daidzein, while only 25% of the European and American populations are capable of doing so . Clostridium, Eggerthella, Slackia, Streptococcus strains, Lactococcus garvieae, and Enterococcus initially convert daidzein to dihydrodaidzein, and the conversion of dihydrodaidzein to tetrahydrodaidzein, and than tetrahydrodaidzein to S-equol.
Changes in the intestinal bacterial population, the use of antibiotics, and changes in diet can alter the ability to produce S-equol (Figure 6).
Figure 6 The transformation of daidzein to S-equol.
Figure 7 The chemical structure of isoflavonoid derivates.
Figure 8 The molecular structure and overlap of 17β-estradiol and S-equol
8. Some Important Herbs that Contain Phytoestrogens
In Traditional Chinese medicine (TCM), several herbs rich in phytoestrogens are used to prevent and cure various diseases such as osteoporosis, cardiovascular diseases, diabetes mellitus, hypertension, hyperlipidemia, tumors, and inflammation. Additionally, 185 herbs are used to treat symptoms of menopause .
Significant amounts of phytoestrogen are found in Agrimonia eupatoria, Angelicae sinensis, Arachis hypogaea, Arctium lappa, Astragalus lentiginosus, Carthamus tinctorius, Cimicifuga racemosa, Crotalaria albida, Coffea Arabica (green), Cucurbita pepo, Foeniculum vulgare, Forsythia koreana, Glycine max, Glycyrrhiza glabra, Glycyrrhiza uralensis, Humulus lupulus, Iresine herbstii, Linum usitatissimum, Matricaria recutita, Medicago sativa, Mucuna sempervirens, Ononis spinose, Panax ginseng, Phaseolus vulgaris, Pisonia umbellifera, Pisum sativum, Polygonum cuspidatum, Pueraria lobate, Rosmarinus officinalis, Sesamum indicum, Silybum marianum, Spatholobus suberectus, Trifolium incarnatum, Trifolium pratense, Triticum aestivum, Triticum vulgare, Vigna radiata, Vigna unguiculata, Vitis berlandieri, Vitis riparia, and Vitis vinifera.
Herbs containing phytoestrogens are important in TCM. In China, Korea, and Japan, herbs have been used for thousands of years to relieve perimenopausal symptoms.
8.1 Angelicae Sinensis
Angelicae sinensis (Oliv.) Diels belongs to the Apiaceae family. Radix Angelicae sinensis is a commonly used Chinese herb, which has traditionally been used to treat dysmenorrhoea and irregular menstruation and as a supportive herb for menopausal complaints. It has an estrogen-like effect on the vaginal mucosa. Its extract competes with estradiol for estrogen-binding and progesterone-binding sites in human myometrial cytosol . The herbal preparation Danggui Buxue Tang was first prescribed by Li Dongyuan in Neiwaishang Bianhuo Lun, in AD 1247 to treat gynecological disorders. This preparation consisted of Radix Astragali (root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, Leguminosae) and Radix Angelicae sinensis (root of Angelica sinensis (Oliv.) Diels, Apiaceae). This herbal preparation was widely used .
The decoction of Buyang Huanwu consists of radix Astragali, radix Angelicae sinensis, rhizoma Ligustici chuanxiong, radix Paeoniae rubra, flos Carthami, semen Persicae, and Lumbricus (Figure 9). The formulation was analyzed by ultrafast HPLC and DADTOF/MS. In total, 54 major components, four C-glycosylquinocalcones, four flavonoid O-glycosides, 16 isoflavones, six monoterpene glycosides, eight saponins, four organic acids, and five amino acids were identified or experimentally characterized based on their retention times.
Figure 9 Isoflavan components of the Buyang Huanwu decoction .
8.2 Flemingia Macrophylla
Flemingia macrophylla (Willd.) Kuntze ex Merr. belongs to the Fabaceae family. The isoflavonoid-rich Flemingia macrophylla extract contains typical compounds of Fabaceae and prenylated isoflavones (Figure 10). Among various types of isoflavones, it also contains a new isoflavone component known as flemiphyllin, as well as several flavonoids that were previously unknown.
The extract of Flemingia macrophylla inhibits elastase activity, promotes the expression of the protein type I procollagen, and attenuates phosphorylation of mitogen-activated protein (MAP) kinase and the expression of matrix-metalloproteinases (MMP-1, –3, and –9); thus, it has an anti-cancer effect. The antioxidants of the drug have ideal anti-aging properties .
Figure 10 The isoflavone component of Flemingia macrophylla.
8.3 Panax Ginseng
Panax ginseng is a perennial plant in the genus Panax of the family Araliaceae. Most ginseng species are native to East Asia. The active components of ginseng include saponins, most of which are glycosides of triterpenoid aglycones and are similar to estradiol. Panax ginseng has several phytoestrogens (Figure 11). Most ginsenosides are metabolized by intestinal bacteria. Ginsenoside-Rb1 acts by binding to the estrogen receptor. This was confirmed by the inhibition of its activity by the specific estrogen receptor antagonist ICI 182,780 .
Ginsenoside-Rh 1 is also weakly estrogenic and can bind to and activate the estrogen receptor. Ginsenoside-Rh1 increases c-fos and pS2 mRNA levels 24 h after treatment, but the effects are weaker than those of 17β-estradiol on MCF-7 breast cancer cells .
The root powder of Panax quinquefolium (American Ginseng) is also used to treat breast cancer.
However, in female SENCAR mice with dimethylbenzanthracene (DMBA)-induced mammary carcinoma, the difference between the control group and the American ginseng-treated group was not statistically significant after 52 weeks of treatment. The American ginseng was less effective than the selective estrogen receptor modulators tamoxifen and ospemifene. The Lady 4 combination contained evening primrose oil, damiana, ginseng, and royal jelly, which was beneficial for women with menopausal syndrome after two and four weeks of treatment, as determined by the outcome of the Menopause Rating Scale-II (MRS-II). The MRS-II score in the Lady 4 combination treated group was significantly better than that of the placebo control group [83,84].
Figure 11 The active ingredients of ginseng.
8.4 Pueraria Lobata
Pueraria lobata (Willd) (kudzu) belongs to the Leguminosae family and is used in TCM. The flowers of Pueraria lobata have two major isoflavones, which include tectoridin and 6”-O-xylosyl-tectoridin, and other isoflavonoids, kakkalide, kakkalidone, puerarin, irisolidone, 6”-O-xylosyl-glycitin, and genistin. It is used to treat intoxication, alcoholic hepatic diseases, and gastrointestinal diseases. The roots of Pueraria lobata contain puerarin, daidzin, daidzein, genistin, and genistein and are effective for treating cardiovascular diseases, osteonecrosis, and neurodegradation. They also have antidiabetic, antiviral, and antioxidant effects and can inhibit rectal ulcers and bleeding (Figure 12) .
Figure 12 The active ingredients of Pueraria lobata.
Tectoridin, 6”-O-xylosyl-tectoridin, kakkalide, and their metabolites have estrogenic effects. Tectoridin metabolites activate estrogen and thyroid hormone receptors . The isoflavonoids from the kudzu root can protect vascular endothelial cells against reactive oxygen species (ROS)-mediated apoptosis and mitochondrial damage . Puerarin is an important isoflavone glycoside. It has low toxicity and strong anticarcinogenic effects. This plant can inhibit the proliferation of different cancer cell lines by modulating different signal transduction pathways, such as NF-κB, PI3K/AKT/mTOR, JNK, MEK/ERK (Raf)-MEK-ERK, and autophagy. The antioxidant molecules produced by the plant can inhibit oxidative stress and inflammation .
8.5 Trifolium Pratense
Trifolium pratense L. belongs to the family Fabaceae. The main active ingredients are biochanin A, formonentin, formononetin, prunetin, genistein, daidzein, isoflavone monogalactosides, and coumestans phytoestrogens .
The therapeutic effects of bioactive ingredients of Trifolium pratense extract on menopausal symptoms have not been proven. The results of published studies do not sufficiently demonstrate their beneficial effects on the breast and endometrium.
Trifolium pratense also contains coumarin derivatives and should be used with caution; they are contraindicated in anticoagulant therapy .
In a study on the properties of Trifolium pratense, the relationships between phytoestrogens, antioxidants, and anti-cancer effects were established. The drug positively affects glucose and lipid metabolism; therefore, it has a protective effect on the cardiovascular system.
Other studies, however, did not consider the plant to be a strong candidate for treating the symptoms of menopause. It also did not improve sexual satisfaction. This plant extract has negative effects on sperm parameters [93,94,95]. Biochanin A is a potent inhibitor of Chlamydia spp. . However, the anti-cancer effect of the extract was reported in several studies .
8.6 Vigna Unguiculata
The cowpea is grown in many tropical parts of the world for human consumption and animal feed. The shoots, leaves, unripe pods, and dry ripe seeds of all varieties are harvested. The health effects of the isoflavonoids of edible cowpea (sand beans and chickpeas) have also been studied .
Osteoporosis can be delayed by consuming cowpea. Daidzein also has anti-osteoporotic effects. It affects osteoblast function, stimulates cell proliferation, and promotes the differentiation of osteoblasts. Daidzein acts by stimulating the activation of the BMP-2/Smads pathway [58,98].
Cowpea is a “functional food” and has a positive effect on health. The concentrations of ascorbic acid, chlorophyll, carotenoids, anthocyanins, flavonoids, and phenolic compounds of cowpea change during cooking, but its antioxidant effects still protect against oxidative damage .
8.7 Glycine Max
Soy (Glycine max (L.) Merril)/Fabaceae) is highly nutritious.
The population of Southeast Asia has been consuming soy for the past 5,000 years; however, it first appeared in Europe in the 17th century. Soybean cultivation in Hungary started only 100 years ago.
In China, Korea, and Japan, the estimated average isoflavone consumption is 20–50 mg/day .
However, not everyone can consume soy. Although soy contains favorable levels of proteins, starch, fatty acids (linolenic acid), simple sugars, crude fiber, amino acids (lysine, methionine, cysteine, threonine, and tryptophan), and isoflavone (daidzein, genistein, and biochanin), it also contains phytic acid and certain proteins that protect against macroorganisms and microorganisms. These proteins, such as β-conglycinin and trypsin inhibitors (Bowman-Birk trypsin-chymotrypsin inhibitor and soybean Kunitz trypsin inhibitor), can cause allergies (atopic dermatitis/eczema) and other side effects (indigestion). Lectins (hemagglutinins) interact with cell surface carbohydrates to damage intestinal mucosal cells and agglutinate red blood cells.
Researchers in China compared the isoflavonoid content of different soybeans and found that the isoflavonoid content in Chinese samples was similar to that in Japanese samples but was considerably lower than that in American samples.
The Chinese herbal preparation made from fermented black soybeans or soybeans had higher isoflavone glucosides and aglycones than those prepared from natural soybeans (Figure 13).
Differences in soy products might also cause a lower rate of breast cancer among Asian women .
Figure 13 The list of soy isoflavones  [daidzein (DAE), glycitein (GLE), genistein (GEE), daidzin (DAI), glycitin (GLI), genistin (GEI), malonylglucosides, 6-O-malonyl-7-O-β-D-daidzin (Mal-DAI), 6-O-malonyl-7-O-β-D-glycitin (Mal-GLI), 6-O-malonyl-7-O-β-D-genistin (Mal-GEI), acetylglucosides, 6-O-acetyl-7-O-β-D-daidzin (Ac-DAI), 6-O-acetyl-7-O-β-D-glycitin (Ac-GLI), and 6-O-acetyl-7-O-β-D-genistin (Ac-GEI).]
9. Experimental and Clinical Studies with Soy Phytoestrogens
Besides isoflavonoids, the soluble and insoluble dietary fiber, phytochemicals, proteins, and peptides in legumes also have several beneficial physiological effects on the treatment of diabetes, hypertension, hyperlipidemia, and anti-inflammatory therapy.
Besides phytoestrogens, soy proteins also have beneficial effects on the human body. The serum cholesterol levels decreased in elderly women with hypercholesterolemia after the daily intake of 5 g of soy for three months .
In a randomized, placebo-controlled study, significant changes occurred in the characteristics of half of the participants with metabolic syndrome compared to the changes in the characteristics of healthy controls. The body weight, body mass index, and LDL-cholesterol levels decreased, and beneficial changes occurred in the lipid profile. Soy consumption significantly reduced the cardiovascular risk and also showed a beneficial effect on the symptoms of metabolic syndrome .
However, in another placebo-controlled randomized clinical trial, coronary calcification was shown to be faster in hormone replacement therapy when there was a greater reduction in plasma residual lipoprotein cholesterol and pre-beta-HDL subpopulation. This suggested that they were predictive factors for coronary heart disease .
The findings of epidemiological studies suggested that the incidence of breast cancer is significantly lower in Asian countries than in the United States or Europe. This phenomenon has also been associated with higher consumption of soy [107,108].
Approximately 10% of the total protein consumed by the Asian population is derived from soy. The concentrations of isoflavone in the urine and serum of women and men and the prostate fluid and serum of men were examined, and it was found that isoflavone concentrations were inversely proportional to the development of breast and prostate cancer .
Mongoloid-type women who emigrated to the US and adopted American eating habits were found to have a higher risk of developing osteoporosis than their counterparts in Asian countries. The differences in mortality are explained by the Asian diet and the consumption of soy-rich foods .
Phytoestrogens reduce bone loss during menopause. In a systematic review and meta-analysis of randomized controlled trials, soy isoflavones were found to have beneficial effects on markers of bone formation; however, extensive multicenter studies are required to confirm these findings, as suggested by the authors .
Sathyapalan et al. conducted a randomized, double-blinded trial and showed favorable significant changes in the markers of bone turnover (β-C-telopeptide and procollagen type 1 N-propeptide) after six months of soy consumption .
A study published in Clinical Nutrition in 2018 quantified plasma phytoestrogen isoflavones (genistein and daidzein) and lignan (enterolactone) by performing liquid chromatography-mass spectrometry in colon cancer patients of both sexes.
In this case-control study with many Vietnamese and Korean colon cancer patients, high plasma levels of isoflavones were associated with a lower risk of colon cancer regardless of ethnic differences, especially in women.
Genistein concentrations were lower in patients with colon cancer. The level of enterolactone was not associated with the risk of colon cancer .
Although several studies have shown the antitumor effect of isoflavones on animals and humans, others have refuted the antitumor effect in recent years [113,114,115]. Although phytoestrogens have many beneficial effects, several studies have shown the harmful effects of some of these active substances.
The benefits of different soy foods and foods containing soy and other plants (meadow testicles, flaxseed, and beans) in improving menopausal symptoms are not clear. In many cases, no significant differences were found after treatment, but the number of reports of conflicting results was unsatisfactory, based on a summary of the results of clinical studies [67,116].
An increase in pre-existing estrogen-dependent breast cancer was found with genistein. Genistein antagonizes the effects of tamoxifen in cancer therapy, thus reducing its efficacy. Also, its use might be contraindicated in women with breast cancer .
A mixture of isoflavonoids isolated from a dietary supplement stimulated the proliferation of MCF-7-E10 (human breast adenocarcinoma cell line) cells in vitro .
The researchers did not rule out the possibility that the concentration of isoflavonoids in breast tissue might be lower than that in studies conducted in vitro, and thus, there might not be an increase in the risk of tumor in vivo.
Another in vitro study was conducted on the effects of genistein alone, or in combination with estradiol and tamoxifen, on the growth of human dysplastic (MCF-10A(1), MCF-ANeoT, MCF-T(6)3B), and malignant MCF-7, MDA-231, and MDA-435) epithelial breast cell lines . Genistein inhibited the growth of dysplastic and malignant epithelial breast cancer cells in vitro, and the addition of tamoxifen had a synergistic/additive inhibitory effect on the proliferation of both cell types. These effects were not modulated by the presence of estrogen receptors .
These findings contradicted the findings of Helferich et al., where phytoestrogens were found to cause metastasis by enhancing cell proliferation. In the groups treated with different isoflavonoids, Ki-67 expression (an indicator of proliferation) occurred at a much higher rate than that without isoflavonoid treatment. The rate was 28% for genistein, 35.9% for daidzein, 28.6% for the equol treated group, and 34.3% for those treated with multiple isoflavonoids. These results suggested that people with cancer are at high risk after phytoestrogen consumption [67,121].
In a 24-week randomized, double-blind study involving few patients, neither soy protein nor isoflavonoids were found to reduce vasomotor symptoms. The differences in the intensity or frequency of hot flushes and night sweats between the groups were not significant. Other symptoms, such as mood swings, vaginal dryness, and decreased libido, occurred; however, the difference between the treatment and placebo groups was not significant .
Together, soy preparation and low-dose hormone therapy did not significantly affect LDL and HDL cholesterol concentrations. These biomarkers are important for cardiovascular diseases .
Since the use of Chinese herbs is expected to increase among women with menopausal symptoms seeking alternative therapies, studies have been conducted by Chinese researchers using well-known databases, including Gynecology and Fertility Group’s Specialized Register of Controlled Trials, Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3), MEDLINE, Embase, CINAHL, AMED, and PsycINFO (from inception to March 2015). Other methods included Current Control Trials, Citation Indices, conference abstracts in the ISI Web of Knowledge, the LILACS database, PubMed, the OpenSIGLE database, and the China National Knowledge Infrastructure database (CNKI, 1999 to 2015).
However, statistical analyses based on the databases studied did not provide sufficient proof that Chinese herbal preparations were as effective as placebo treatment or hormone replacement therapy in relieving vasomotor symptoms. The safety effects were also inconclusive, and further studies using randomized controlled trials need to be conducted .
As no reliable data based on clinical trials are available, future studies should aim to obtain reproducible results regarding menopause and the quality and dose of treatments administered .
Herbal preparations are often marketed as food supplements or homeopathic remedies, and thus, clinical trials by manufacturers and distributors are not mandatory for selling them; such clinical trials are generally not performed. Therefore, rigorous and systematic efficacy studies need to be conducted to obtain conclusive results regarding the effects of herbal preparations .
In this review, we summarized the general [6,11,20] and specific  knowledge regarding phytoestrogens and evaluated the advantages and disadvantages of hormone replacement therapy and phytotherapy in menopausal syndrome. We also briefly summarized the structure and grouping of estrogens and phytoestrogens, especially the bioavailability of isoflavonoids [35,36]. Here, we also showed the effect of phytoestrogens on signal transduction pathways based on recent studies on molecular biology [23,44,45,49,51,58,98].
Diseases and conditions such as osteoporosis, cardiovascular diseases, diabetes, high blood pressure, hyperlipidemia, and sexual problems impair the quality of life. Thus, information and techniques of medicine and phytotherapy can be applied to alleviate discomfort and even life-threatening conditions [67,68,98].
Applied estrogen treatment initially appeared to be a good option, although it caused severe somatic symptoms in many women. Unfortunately, it increased the risk of breast cancer, thromboembolic and cardiovascular events, stroke, and cholecystopathy. A combination treatment using estrogen and progestin was also ineffective [69,71].
Therefore, women tried phytotherapeutic options, such as traditional Chinese medicine, for natural remedies. The popularity of hormone replacement/alternative therapies has also grown significantly, as indicated by the turnover .
However, the biggest problem with phytotherapy treatment is the lack of well-designed randomized clinical trials and information on the efficacy and safety in most cases .
Traditional Chinese medicine is an effective healing method based on 3,000 years of constantly evolving experience, which is now gaining popularity not only in the Far East but also in many other parts of the world. More people have started using Chinese phytotherapeutic formulations in Western countries because synthetic drugs and molecular therapies are often ineffective and have severe side effects and cross-reactions; therefore, they cannot be used in polymorbid patients. However, not knowing or misinterpreting the philosophy and practice of traditional Chinese treatments often leads to ineffectiveness and poisoning.
The biggest problem is that the original Chinese descriptions are often poorly translated (e.g., misspelled drug or product names, incorrect preparation methods, and incorrect dose/therapeutic time); without basic knowledge of TCM, it is difficult to interpret and implement therapeutic procedures .
Another reason is that although TCM is prevalent, the therapeutic procedure of TCM has not been incorporated into the official health care system in the EU and some regions of North America .
The main reason for the fundamental difference between Chinese Medicine formulations and Western medicine is the differences in the starting points, subjects, and techniques of research, the methodological approach, and the theoretical characteristics. These reasons have delayed the development of Chinese Medicine formulations in these regions .
In China, over the last two decades, advanced analytical and molecular biological approaches have been used, and efforts have been made to standardize TCM formulations, although some problems persist [126,128].
For example, studies are being conducted using Chinese herbal active ingredients to decipher the operation of Chinese traditional principles in association with groups from the Eötvös Loránd University (Budapest, Hungary) and the University of Cambridge using Drug Profile Matching, an affinity fingerprint-based in silico drug repositioning approach that can quantitatively predict the overall effect profile of compounds through probability scores [129,130].
It is challenging for practitioners of Western medicine and pharmacognosy to integrate the values of Chinese phytotherapy with the therapy of patients under the pressure of mapping the human genome and the differences in therapeutic ideologies.
It is also challenging for TCM practitioners to combine new molecular biological knowledge with empirically-based and well-functioning approaches. However, research and technical progress can help these different approaches to work together .
Interestingly, the American Cancer Institute (AICR) has cited the results of studies on humans that soy consumption is safe for breast cancer survivors. (Content last updated: 8 April 2021) .
The combination of age-old observations and modern empirical findings might enhance the therapeutic efficacy of phytoestrogens.
The authors contributed equally to this work.
The authors declare that they have no conflict of interest.
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