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Summary of Intended Changes:

We intend to expand the information presented in this article and organize it into sections. These will include a section containing the background information already presented in the article, including the natural sources of coumesterol and its chemical properties. We will also be adding a section including its biological effects, including those related to the nervous system, those related to the reproductive system, fertility, and development, and possibly those related to metabolism. We also intend to include a section regarding the current studies of its potential impact, both positive and negative, on health issues such as breast cancer and menopause.

Potential Topic Headlines/Article Outline

Original Article/Leading Paragraph

Coumestrol is a natural organic compound in the class of phytochemicals known as coumestans. Coumestrol was first identified by E. M. Bickoff in alfalfa in 1957.^[1] It has garnered research interest because of its estrogenic activity and its 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. ^[2]

Coumestrol is a phytoestrogen, mimicking the biological activity of estrogens. Coumestrol has about the same binding affinity for the ER-β estrogen receptor as 17β-estradiol, but much less affinity than 17α-estradiol, although the estrogenic potency of coumestrol at both receptors is much less than that of 17β-estradiol.^[3]

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 hydroxysteroid dehydrogenase.^[4] These enzymes are involved in the biosynthesis of steroid hormones, and inhibition of these enzymes results in the modulation of hormone production.^[5]

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 it 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. ^[6]

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)
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
Red Clover	1322.00
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

^[2]

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. Studies of phytoestrogen intake indicate that most human diets result in a negligible intake of coumestrol. ^[7]

Biological Effects

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 exposed to who nursed from mothers on a diet of coumestrol 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. ^[8] ^[9]

Reproductive Tract

Coumestrol has been shown to accelerate the onset of puberty in mice. ^[7] 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. ^[9] A high coumestrol diet has also been shown to induce early development of the vulva and udder of female lambs. In addition to anatomical effects, 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. ^[6]

Skeletal System

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. ^[9]

Genotoxicity

Coumestrol has been shown to have clastogenic properties. Studies have shown that coumestrol is a mutagen and induces formation of micronuclei in V79 hamster cells as well as human lymphoblastoid cells in a dose-dependent manner. Exposure to coumestrol also causes single stranded breaks in hamster DNA. ^[10]

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. ^[11]

Improving Therapeutic Efficacy

Menopause

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.^[12] 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. ^[8]

Breast Cancer

Coumestrol and other phytoestrogens have also been investigated as a possible substitute for hormone therapy 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. ^[13] 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.^[14]

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. ^[11] 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. ^[6]

References

^ E. M. Bickoff, A. N. Booth, R. L. Lyman, A. L. Livingston, C. R. Thompson, and F. Deeds (1957). "Coumestrol, a New Estrogen Isolated from Forage Crops". Science. 126 (3280): 969–970. doi:10.1126/science.126.3280.969-a. PMID 13486041.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b Bhagwat, Seema; Haytowitz, David; Holden, Joanne (September 2008). USDA Database for the Isoflavone Content of Selected Foods (PDF) (Release 2.0 ed.). Beltsville, Maryland: U.S. Department of Agriculture. Retrieved 10 March 2015.
^ Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA (1998). "Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta". Endocrinology. 139 (10): 4252–4263. doi:10.1210/endo.139.10.6216. PMID 9751507.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Blomquist CH, Lima PH, Hotchkiss JR (2005). "Inhibition of 3a-hydroxysteoid dehydogenase (3a-HSD) activity of human lung microsomes by genistein, daidzein, coumestrol and C18-, C19- and C21 hydroxysteroids and ketosteroids". Steroids. 70 (8): 507–514. doi:10.1016/j.steroids.2005.01.004. PMID 15894034.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Amr Amin and Michael Buratovich (2007). "The Anti-Cancer Charm of Flavonoids: A Cup-of-Tea Will Do!". Recent Patents on Anti-Cancer Drug Discovery. 2 (2): 109–117. doi:10.2174/157489207780832414. PMID 18221056.
^ ^a ^b ^c United States Department of Agriculture (2003). Studies on the Chemical and Biological Properties of Coumestrol and Related Compounds. US Government Printing Office. p. 47-67.
^ ^a ^b Shaw, Ian (March 2009). Endocrine-disrupting chemicals in food. Cambridge: Woodhead Publishing Limited. ISBN 9781845695743. {{cite book}}: |access-date= requires |url= (help)
^ ^a ^b Whitten, Patricia; Patisaul, Heather; Young, Larry (2002). "Neurobehavioural actions of coumestrol and related isoflavonoids in rodents". Neurotoxicology and Teratology. 24 (1): 47-54.
^ ^a ^b ^c Naz, Rajesh K. (2005). Endocrine disruptors : effects on male and female reproductive systems (2nd ed. ed.). Boca Raton: CRC Press. ISBN 9780849322815. {{cite book}}: |access-date= requires |url= (help); |edition= has extra text (help)
^ Stopper, H; Schmitt, E; Kobras, K (1 July 2005). "Genotoxicity of phytoestrogens". Mutation research. 574 (1–2): 139–55. PMID 15914213.
^ ^a ^b Preedy, edited by Victor R. (2013). Isoflavones chemistry, analysis, function and effects. Cambridge, U.K.: Royal Society of Chemistry. pp. 518–526. ISBN 978-1-84973-509-4. {{cite book}}: |access-date= requires |url= (help); |first1= has generic name (help)
^ Lethaby, A; Marjoribanks, J; Kronenberg, F; Roberts, H; Eden, J; Brown, J (10 December 2013). "Phytoestrogens for menopausal vasomotor symptoms". The Cochrane database of systematic reviews. 12: CD001395. PMID 24323914.
^ Mense, SM; Hei, TK; Ganju, RK; Bhat, HK (April 2008). "Phytoestrogens and breast cancer prevention: possible mechanisms of action". Environmental health perspectives. 116 (4): 426–33. PMID 18414622.
^ Obiorah, IE; Fan, P; Jordan, VC (September 2014). "Breast cancer cell apoptosis with phytoestrogens is dependent on an estrogen-deprived state". Cancer prevention research (Philadelphia, Pa.). 7 (9): 939–49. PMID 24894196.