Names | |
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IUPAC name 3,9-Dihydroxypterocarp-6a(11a)-en-6-one | |
Systematic IUPAC name 3,9-Dihydroxy-6H-[1]benzofuro[3,2-c][1]benzopyran-6-one | |
Identifiers | |
3D model (JSmol) | |
ChEBI | |
ChEMBL | |
ChemSpider | |
ECHA InfoCard | 100.006.842 |
EC Number |
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KEGG | |
PubChem CID | |
UNII | |
CompTox Dashboard (EPA) | |
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Properties | |
C15H8O5 | |
Molar mass | 268.224 g·mol−1 |
Melting point | 385 °C (725 °F; 658 K) (decomposes) [1] |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Coumestrol is a natural organic compound in the class of phytochemicals known as coumestans. Coumestrol was first identified as a compound with estrogenic properties by E. M. Bickoff in ladino clover and alfalfa in 1957. [2] It has garnered research interest because of its estrogenic activity and prevalence in some foods, including soybeans, brussels sprouts, spinach and a variety of legumes. The highest concentrations of coumestrol are found in clover, Kala Chana (a type of chick pea), and Alfalfa sprouts. [3]
Coumestrol is a phytoestrogen, mimicking the biological activity of estrogens. Phytoestrogens are able to pass through cell membranes due to their low molecular weight and stable structure, and they are able to interact with the enzymes and receptors of cells. [4] Coumestrol binds to the ERα and ERβ with similar affinity to that of estradiol (94% and 185% of the relative binding affinity of estradiol at the ERα and ERβ, respectively), [5] although the estrogenic activity of coumestrol at both receptors is much less than that of estradiol. [6] In any case, coumestrol has estrogenic activity that is 30 to 100 times greater than that of isoflavones. [7]
The chemical shape of coumestrol orients its two hydroxy groups in the same position as the two hydroxy groups in estradiol, allowing it to inhibit the activity of aromatase and 3α-hydroxysteroid dehydrogenase. [8] These enzymes are involved in the biosynthesis of steroid hormones, and inhibition of these enzymes results in the interference with hormone metabolism. [9]
Levels of coumestrol within individual plants of the same species are variable. Studies of coumestrol levels in alfalfa suggest that there may be a positive correlation between coumestrol production and infection of the plant by viruses, bacteria, and fungi. Higher levels of coumestrol are also found in plants which had been damaged by aphids. Further study is required to fully explain the cause of the correlation between damage, infection, and coumestrol levels. [10]
According to the United States Department of Agriculture and Iowa State University database on isoflavanes and coumestrol, coumestrol is found in the following food items:
Food Item | Coumestrol Level (mg/100g) |
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Large, dry Lima beans | 0.14 |
Raw Pinto Beans | 1.80 |
Dry Kala Chana | 6.13 |
Alfalfa Sprouts | 1.60 |
Raw Clover Sprouts | 14.08 |
Soy Sprouts | 0.34 |
Mature Soy Beans | 0.02 |
Unfortified Original and Vanilla Soy milk | 0.81 |
Firm Tofu Prepared with Calcium Sulfate and Magnesium Chloride | 0.12 |
Doughnuts with Soy Flour of Protein | 0.24 |
Based on extrapolation from studies done on animals, the maximum tolerable daily intake of coumestrol for human beings has been estimated at 22 μg per kg of body mass. This was calculated by extrapolating from the lowest level at which adverse effects were seen in animals. Although due to the variability of the human diet, the exact amount of coumestrol the average person consumes has not been calculated, studies of phytoestrogen intake suggest that most human diets result in a negligible intake of coumestrol relative to the maximum tolerable daily intake. [12]
Because coumestrol is an estrogen mimic, it is an endocrine disruptor with the potential to affect all organ systems that are regulated hormonally via estrogens.
Coumestrol and other phytoestrogens have been shown to have an effect on sexual behavior in rats by antagonizing the action of estrogen within the brain; male rats that nursed from females with coumestrol in their diets were both less likely to mount a female rat and less likely to ejaculate, despite producing normal levels of testosterone. Exposure produced similar decreases of sexual behavior in female rats, as a result of the disruption of estrogen dependent gene expression in the brain. Effects were seen in three areas of the hypothalamus, the ventromedial nucleus, the paraventricular nucleus, and the medial preoptic area, all of which play a role in sexual behavior and sexual activity. [13] [14] Female rats that were exposed to coumestrol neonatally did not adopt the lordosis position as much as those that were not exposed to coumestrol. [15]
Coumestrol has been shown to accelerate the onset of puberty in mice. [12] Exposure to coumestrol immediately after birth resulted in an initial increase in uterine weight. However, continued exposure inhibited the growth of the uterus and decreased levels of estrogen receptors within uterine tissue. The rats also showed altered vaginal development including cornification and metaplasia of vaginal tissue, and delayed opening of the vagina. [14] When neonatal female mice were treated with coumestrol, similar reproductive irregularities occurred, and at 22 months old, atypical collagen distribution was observed in the uterine wall. [15] When 2 day old male Wistar rats are injected with coumestrol daily, they exhibit a decrease in size in the lumens of their seminiferous tubules and germ cells go through increased rates of apoptosis. When bulls graze on pastures containing coumestrol, metaplasia occurs in the prostate and bulbourethral glands, and sperm maturation is suppressed. Female cows that consumed alfalfa experienced lower pregnancy rates and spontaneous abortions, as well as abnormal estrogen levels during pregnancy. [16] A high coumestrol diet has also been shown to induce early development of the vulva and udder of female lambs. In addition to these anatomical abnormalities, exposure to coumestrol has also been shown to alter the estrus cycle of a number of animals, including cows and sheep, resulting in lower rates of fertility. [10]
Coumestrol has been shown to decrease bone resorption and promote the mineralization of bone in vitro and in vivo; daily injections of coumestrol were shown to reduce bone loss in rats who had undergone an ovariectomy. [14]
Coumestrol has been shown to have clastogenic properties at a certain concentration.[ specify ]. Studies have shown that coumestrol is a mutagen and induces formation of micronuclei in hamster cells of the V79 cell line as well as human lymphoblastoid cells in a dose-dependent manner. Exposure to coumestrol also causes single stranded breaks in hamster DNA, compromising genome stability. [17]
Studies have shown that coumestrol has beneficial properties on carbohydrate metabolism in ovariectomized rats, decreasing glycogen levels in skeletal muscle. There is also data indicating that coumestrol lowers plasma cholesterol levels in chicks. These results point to a possibility of coumestrol having a positive role to play against human obesity and diabetes in the future. [18]
Coumestrol and other phytoestrogens are sometimes used as a substitute for hormone therapy in the treatment of menopausal symptoms such as hot flashes and night sweats. However, studies have indicated that phytoestrogen-enriched foods and supplements are not necessarily effective against these symptoms. [19] In addition, studies indicate that coumestrol and other phytoestrogens have an antiestrogenic effect in the brain and, as a result, do not produce the mental health benefits which are seen in estrogen replacement therapy. [13]
Coumestrol and other phytoestrogens have also been investigated as a possible substitute for hormone therapy and chemotherapy in breast cancer patients. The results of various studies regarding the use of phytoestrogens in treating breast cancer have been somewhat contradictory and ambiguous, and as a result, researchers cannot clearly define phytoestrogens like coumestrol as being chemoprotective agents or potentially having negative effects, such as inducing further growth of existing breast cancer tumors by activating ERα receptors. [20] Researchers at Georgetown University Medical Center have investigated this matter and concluded that phytoestrogens may be used as an effective treatment for breast cancer because of their apoptotic properties, but that it is only safe to do so after menopause, when women have a much lower level of estrogen in their bodies, or when used conjunctively with anti-estrogen therapies. [21]
Most research on the biological effects of coumestrol has been conducted on animals because of ethical concerns. There is a need for more human studies to better understand potential human health impacts due to exposure. [18] In addition, further research is required to fully understand the biosynthesis pathway of coumestrol, although it is believed to be similar to that of flavones and isoflavones. Further research is required to understand the exact nature of the relationship between the levels of coumestrol in a plant and the plant's response to pathogens. [10]
Estrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol (E4) is produced only during pregnancy.
Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible for the development of female secondary sexual characteristics such as the breasts, widening of the hips and a female pattern of fat distribution. It is also important in the development and maintenance of female reproductive tissues such as the mammary glands, uterus and vagina during puberty, adulthood and pregnancy. It also has important effects in many other tissues including bone, fat, skin, liver, and the brain.
Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a history of recurrent miscarriage, hormone therapy for menopausal symptoms and estrogen deficiency, treatment of prostate cancer and breast cancer, and other uses. By 2007, it was only used in the treatment of prostate cancer and breast cancer. In 2011, Hoover and colleagues reported on adverse health outcomes linked to DES including infertility, miscarriage, ectopic pregnancy, preeclampsia, preterm birth, stillbirth, infant death, menopause prior to age 45, breast cancer, cervical cancer, and vaginal cancer. While most commonly taken by mouth, DES was available for use by other routes as well, for instance, vaginal, topical, and by injection.
Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized from cholesterol and secreted mainly from the gonads, though they can also be formed from adrenal androgens in adipose tissue. Relative to estradiol, both estrone and estriol have far weaker activity as estrogens. Estrone can be converted into estradiol, and serves mainly as a precursor or metabolic intermediate of estradiol. It is both a precursor and metabolite of estradiol.
Hot flashes are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and may typically last from two to 30 minutes for each occurrence.
A phytoestrogen is a plant-derived xenoestrogen not generated within the endocrine system, but consumed by eating plants or manufactured foods. Also called a "dietary estrogen", it is a diverse group of naturally occurring nonsteroidal plant compounds that, because of its structural similarity to estradiol (17-β-estradiol), have the ability to cause estrogenic or antiestrogenic effects. Phytoestrogens are not essential nutrients because their absence from the diet does not cause a disease, nor are they known to participate in any normal biological function. Common foods containing phytoestrogens are soy protein, beans, oats, barley, rice, coffee, apples, carrots.
Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–antagonists, SERMs are more tissue-specific, allowing them to selectively inhibit or stimulate estrogen-like action in various tissues.
Equol (4',7-isoflavandiol) is an isoflavandiol estrogen metabolized from daidzein, a type of isoflavone found in soybeans and other plant sources, by bacterial flora in the intestines. While endogenous estrogenic hormones such as estradiol are steroids, equol is a nonsteroidal estrogen. Only about 30–50% of people have intestinal bacteria that make equol.
Estrogen receptors (ERs) are proteins found in cells that function as receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen receptors, namely ERα and ERβ, which belong to the nuclear receptor family. The second class consists of membrane estrogen receptors (mERs), such as GPER (GPR30), ER-X, and Gq-mER, which are primarily G protein-coupled receptors. This article focuses on the nuclear estrogen receptors.
Genistein (C15H10O5) is a naturally occurring compound that structurally belongs to a class of compounds known as isoflavones. It is described as an angiogenesis inhibitor and a phytoestrogen.
G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the GPER gene. GPER binds to and is activated by the female sex hormone estradiol and is responsible for some of the rapid effects that estradiol has on cells.
Estrogen receptor beta (ERβ) also known as NR3A2 is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by the ESR2 gene.
Coumestan is a heterocyclic organic compound. Coumestan forms the central core of a variety of natural compounds known collectively as coumestans. Coumestans are oxidation products of pterocarpan that are similar to coumarin. Coumestans, including coumestrol, a phytoestrogen, are found in a variety of plants. Food sources high in coumestans include split peas, pinto beans, lima beans, and especially alfalfa and clover sprouts.
Estetrol (E4), or oestetrol, is one of the four natural estrogenic steroid hormones found in humans, along with estrone (E1), estradiol (E2), and estriol (E3). Estetrol is a major estrogen in the body. In contrast to estrone and estradiol, estetrol is a native estrogen of fetal life. Estetrol is produced exclusively by the fetal liver and is found in detectable levels only during pregnancy, with relatively high levels in the fetus and lower levels in the maternal circulation.
Genistin is an isoflavone found in a number of dietary plants like soy and kudzu. It was first isolated in 1931 from the 90% methanol extract of a soybean meal, when it was found that hydrolysis with hydrochloric acid produced 1 mole each of genistein and glucose. Chemically it is the 7-O-beta-D-glucoside form of genistein and is the predominant form of the isoflavone naturally occurring in plants. In fact, studies in the 1970s revealed that 99% of the isoflavonoid compounds in soy are present as their glucosides. The glucosides are converted by digestive enzymes in the digestive system to exert their biological effects. Genistin is also converted to a more familiar genistein, thus, the biological activities including antiatherosclerotic, estrogenic and anticancer effects are analogous.
4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) is a metabolite of bisphenol A (BPA). MBP has potent estrogenic activity in vitro and in vivo, up to thousandfold stronger than BPA. It may also play a role in neuronal cell apoptosis and may increase risk for several forms of cancer.
8-Prenylnaringenin (8-PN; also known as flavaprenin, (S)-8-dimethylallylnaringenin, hopein, or sophoraflavanone B) is a prenylflavonoid phytoestrogen. It is reported to be the most estrogenic phytoestrogen known. The compound is equipotent at the two forms of estrogen receptors, ERα and ERβ, and it acts as a full agonist of ERα. Its effects are similar to those of estradiol, but it is considerably less potent in comparison.
Neurodegenerative diseases can disrupt the normal human homeostasis and result in abnormal estrogen levels. For example, neurodegenerative diseases can cause different physiological effects in males and females. In particular, estrogen studies have revealed complex interactions with neurodegenerative diseases. Estrogen was initially proposed to be a possible treatment for certain types of neurodegenerative diseases but a plethora of harmful side effects such as increased susceptibility to breast cancer and coronary heart disease overshadowed any beneficial outcomes. On the other hand, Estrogen Replacement Therapy has shown some positive effects with postmenopausal women. Estrogen and estrogen-like molecules form a large family of potentially beneficial alternatives that can have dramatic effects on human homeostasis and disease. Subsequently, large-scale efforts were initiated to screen for useful estrogen family molecules. Furthermore, scientists discovered new ways to synthesize estrogen-like compounds that can avoid many side effects.
E-SCREEN is a cell proliferation assay based on the enhanced proliferation of human breast cancer cells (MCF-7) in the presence of estrogen active substances. The E-SCREEN test is a tool to easily and rapidly assess estrogenic activity of suspected xenoestrogens. This bioassay measures estrogen-induced increase of the number of human breast cancer cell, which is biologically equivalent to the increase of mitotic activity in tissues of the genital tract. It was originally developed by Soto et al. and was included in the first version of the OECD Conceptual Framework for Testing and Assessment of Endocrine Disrupters published in 2012. However, due to failed validation, it was not included in the updated version of the framework published in 2018.
Estetrol (E4) is an estrogen medication and naturally occurring steroid hormone which is used in combination with a progestin in combined birth control pills and is under development for various other indications. These investigational uses include menopausal hormone therapy to treat symptoms such as vaginal atrophy, hot flashes, and bone loss and the treatment of breast cancer and prostate cancer. It is taken by mouth.