Coumestrol is a natural
organic compound
In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...
in the class of
phytochemical
Phytochemicals are chemical compounds produced by plants, generally to help them resist fungi, bacteria and plant virus infections, and also consumption by insects and other animals. The name comes . Some phytochemicals have been used as poisons ...
s known as
coumestan
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, includ ...
s. Coumestrol was first identified as a compound with estrogenic properties by E. M. Bickoff in ladino
clover
Clover or trefoil are common names for plants of the genus ''Trifolium'' (from Latin ''tres'' 'three' + ''folium'' 'leaf'), consisting of about 300 species of flowering plants in the legume or pea family Fabaceae originating in Europe. The genus ...
and
alfalfa
Alfalfa () (''Medicago sativa''), also called lucerne, is a perennial flowering plant in the legume family Fabaceae. It is cultivated as an important forage crop in many countries around the world. It is used for grazing, hay, and silage, as w ...
in 1957. It has garnered research interest because of its estrogenic activity and prevalence in some foods, including
soybean
The soybean, soy bean, or soya bean (''Glycine max'') is a species of legume native to East Asia, widely grown for its edible bean, which has numerous uses.
Traditional unfermented food uses of soybeans include soy milk, from which tofu an ...
s,
brussels sprout
The Brussels sprout is a member of the Gemmifera cultivar group of cabbages (''Brassica oleracea''), grown for its edible buds. The leaf vegetables are typically 1.5–4.0 cm (0.6–1.6 in) in diameter and resemble miniature cabbages ...
s,
spinach
Spinach (''Spinacia oleracea'') is a leafy green flowering plant native to central and western Asia. It is of the order Caryophyllales, family Amaranthaceae, subfamily Chenopodioideae. Its leaves are a common edible vegetable consumed either f ...
and a variety of
legume
A legume () is a plant in the family Fabaceae (or Leguminosae), or the fruit or seed of such a plant. When used as a dry grain, the seed is also called a pulse. Legumes are grown agriculturally, primarily for human consumption, for livestock f ...
s. The highest concentrations of coumestrol are found in
clover
Clover or trefoil are common names for plants of the genus ''Trifolium'' (from Latin ''tres'' 'three' + ''folium'' 'leaf'), consisting of about 300 species of flowering plants in the legume or pea family Fabaceae originating in Europe. The genus ...
, Kala Chana (a type of
chick pea
The chickpea or chick pea (''Cicer arietinum'') is an annual legume of the family Fabaceae, subfamily Faboideae. Its different types are variously known as gram" or Bengal gram, garbanzo or garbanzo bean, or Egyptian pea. Chickpea seeds are hi ...
), and
Alfalfa sprouts.
Coumestrol is a
phytoestrogen
A phytoestrogen is a plant-derived xenoestrogen (see estrogen) 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 nonstero ...
, mimicking the
biological activity
In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...
of
estrogen
Estrogen or oestrogen 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 acti ...
s. 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.
Coumestrol binds to the
ERα
Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein)
that is activated by the sex ...
and
ERβ
Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) 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 ...
with similar
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Partn ...
to that of
estradiol
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...
(94% and 185% of the
relative binding affinity
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mole ...
of estradiol at the ERα and ERβ, respectively),
although the estrogenic activity of coumestrol at both receptors is much less than that of estradiol. In any case, coumestrol has estrogenic activity that is 30 to 100 times greater than that of isoflavones.
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
Inhibitor or inhibition may refer to:
In biology
* Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity
* Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...
the activity of
aromatase
Aromatase (), also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze many ...
and
3α-hydroxysteroid dehydrogenase. These enzymes are involved in the biosynthesis of
steroid
A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
hormones, and inhibition of these enzymes results in the interference with hormone
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
.
Natural sources and dietary intake
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
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
,
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
, and
fungi
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
. Higher levels of coumestrol are also found in plants which had been damaged by
aphids
Aphids are small sap-sucking insects and members of the superfamily Aphidoidea. Common names include greenfly and blackfly, although individuals within a species can vary widely in color. The group includes the fluffy white woolly aphids. A t ...
. Further study is required to fully explain the cause of the correlation between damage, infection, and coumestrol levels.
According to the
United States Department of Agriculture
The United States Department of Agriculture (USDA) is the United States federal executive departments, federal executive department responsible for developing and executing federal laws related to farming, forestry, rural economic development, ...
and
Iowa State University
Iowa State University of Science and Technology (Iowa State University, Iowa State, or ISU) is a public land-grant research university in Ames, Iowa. Founded in 1858 as the Iowa Agricultural College and Model Farm, Iowa State became one of the n ...
database on
isoflavanes and coumestrol, coumestrol is found in the following food items:
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.
Biological effects on mammals
Because coumestrol is an estrogen mimic, it is an
endocrine disruptor
Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine (or hormonal) systems. These disruptions can cause c ...
with the potential to affect all organ systems that are regulated hormonally via estrogens.
Nervous system
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
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...
. 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 hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
, the
ventromedial nucleus
The ventromedial nucleus of the hypothalamus (VMN, also sometimes referred to as the ventromedial hypothalamus, VMH) is a Nucleus (neuroanatomy), nucleus of the hypothalamus. "The ventromedial hypothalamus (VMH) is a distinct morphological nucleu ...
, the
paraventricular nucleus
The paraventricular nucleus (PVN, PVA, or PVH) is a nucleus in the hypothalamus. Anatomically, it is adjacent to the third ventricle and many of its neurons project to the posterior pituitary. These projecting neurons secrete oxytocin and a smaller ...
, and the
medial preoptic area
The preoptic area is a region of the hypothalamus. MeSH classifies it as part of the anterior hypothalamus. TA lists four nuclei in this region, (medial, median, lateral, and periventricular).
Functions
The preoptic area is responsible for ther ...
, all of which play a role in sexual behavior and sexual activity.
Female rats that were exposed to coumestrol
neonatal
An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...
ly did not adopt the
lordosis
Lordosis is historically defined as an ''abnormal'' inward curvature of the lumbar spine. However, the terms ''lordosis'' and ''lordotic'' are also used to refer to the normal inward curvature of the lumbar and cervical regions of the human spi ...
position as much as those that were not exposed to coumestrol.
Reproductive system
Coumestrol has been shown to accelerate the onset of puberty in mice.
Exposure to coumestrol immediately after birth resulted in an initial increase in uterine weight. However, continued exposure inhibited the growth of the
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
and decreased levels of
estrogen receptors
Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen ( 17β-estradiol). Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the ...
within uterine tissue. The rats also showed altered vaginal development including
cornification
Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. Alpha-keratin (α-keratin) is a type of keratin found in vertebrates. It is the key structural material making up scales, hair, nails, feathers, hor ...
and
metaplasia
Metaplasia ( gr, "change in form") is the transformation of one differentiated cell type to another differentiated cell type. The change from one type of cell to another may be part of a normal maturation process, or caused by some sort of abno ...
of vaginal tissue, and delayed opening of the vagina.
When
neonatal
An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...
female mice were treated with coumestrol, similar reproductive irregularities occurred, and at 22 months old, atypical
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
distribution was observed in the uterine wall.
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
Seminiferous tubules are located within the testes, and are the specific location of meiosis, and the subsequent creation of male gametes, namely spermatozoa. Structure
The epithelium of the tubule consists of a type of sustentacular cells known ...
and germ cells go through increased rates of
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
. When bulls graze on pastures containing coumestrol, metaplasia occurs in the
prostate
The prostate is both an Male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, ...
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.
A high coumestrol diet has also been shown to induce early development of the
vulva
The vulva (plural: vulvas or vulvae; derived from Latin for wrapper or covering) consists of the external sex organ, female sex organs. The vulva includes the mons pubis (or mons veneris), labia majora, labia minora, clitoris, bulb of vestibu ...
and
udder
An udder is an organ formed of two or four mammary glands on the females of dairy animals and ruminants such as cattle, goats, and sheep. An udder is equivalent to the breast in primates and elephantine pachyderms. The udder is a single mass han ...
of female lambs. In addition to these anatomical abnormalities, exposure to coumestrol has also been shown to alter the
estrus
The estrous cycle (, originally ) is the set of recurring physiological changes that are induced by reproductive hormones in most mammalian therian females. Estrous cycles start after sexual maturity in females and are interrupted by anestrous p ...
cycle of a number of animals, including cows and sheep, resulting in lower rates of fertility.
Skeletal system
Coumestrol has been shown to decrease
bone resorption
Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood.
The osteoclasts are multi-nucleated ...
and promote the
mineralization of bone
Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by Cell (biology), cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes ...
''in vitro'' and ''in vivo''; daily injections of coumestrol were shown to reduce bone loss in rats who had undergone an
ovariectomy
Oophorectomy (; from Greek , , 'egg-bearing' and , , 'a cutting out of'), historically also called ''ovariotomy'' is the surgical removal of an ovary or ovaries. The surgery is also called ovariectomy, but this term is mostly used in reference t ...
.
Genotoxicity
Coumestrol has been shown to have
clastogen
A clastogen is a mutagenic agent that disturbs normal DNA related processes or directly causes DNA strand breakages, thus causing the Deletion (genetics), deletion, Insertion (genetics), insertion, or rearrangement of entire chromosome sections. T ...
ic properties at a certain concentration.. Studies have shown that coumestrol is a
mutagen
In genetics, a mutagen is a physical or chemical agent that permanently changes nucleic acid, genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can ca ...
and induces formation of
micronuclei
Micronucleus is the name given to the small nucleus that forms whenever a chromosome or a fragment of a chromosome is not incorporated into one of the daughter nuclei during cell division. It usually is a sign of genotoxic events and chromosomal i ...
in hamster cells of the V79 cell line as well as human
lymphoblastoid
__NOTOC__
A lymphoblast is a modified naive lymphocyte with altered cell morphology. It occurs when the lymphocyte is activated by an antigen (from antigen-presenting cells) and increased in volume by nucleus and cytoplasm growth as well as new mRN ...
cells in a dose-dependent manner. Exposure to coumestrol also causes single stranded breaks in hamster DNA, compromising genome stability.
Metabolism
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.
Menopause
Coumestrol and other phytoestrogens are sometimes used as a substitute for hormone therapy in the treatment of
menopausal symptoms
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
such as hot flashes and night sweats. However, studies have indicated that phytoestrogen-enriched foods and supplements are not necessarily effective against these symptoms. In addition, studies indicate that coumestrol and other phytoestogens 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.
Breast cancer
Coumestrol and other phytoestrogens have also been investigated as a possible substitute for hormone therapy and
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
in
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
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.
Researchers at
Georgetown University Medical Center
Georgetown University Medical Center is a biomedical research and educational organization that responsible for over 80% of Georgetown University's sponsored research funding and is led by Edward B. Healton, MD, the Executive Vice President for He ...
have investigated this matter and concluded that phytoestrogens may be used as an effective treatment for breast cancer because of their
apoptotic
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...
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.
Current and future research
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.
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
Flavones (from Latin ''flavus'' "yellow") are a class of flavonoids based on the backbone of 2-phenylchromen-4-one (2-phenyl-1-benzopyran-4-one) (as shown in the first image of this article).
Flavones are common in foods, mainly from spices, and ...
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.
References
Further reading
*
{{Estrogen receptor modulators
3α-Hydroxysteroid dehydrogenase inhibitors
Aromatase inhibitors
Coumestans
Phytoestrogens
Selective ERβ agonists
Phenols