Health Care Professional Information
Common Name
Cow clover, Wild clover, Purple clover Beebread, Cow grass, Meadow clover, Purple clover
Clinical Summary
Red clover is a perennial herb traditionally used to treat skin disorders such as psoriasis and eczema, whooping cough, and mastitis. It contains compounds known as isoflavones that act as phytoestrogens. A Red clover isoflavone extract is widely promoted as a dietary supplement to relieve menopausal symptoms.
In vitro studies indicate that red clover extract acts as an estrogen agonist and stimulates proliferation of ER positive breast cancer cells (1). However, Biochinin A, a red clover isoflavone, was shown to inhibit aromatase activity and expression (2), thereby conferring a protective effect. In other studies, isoflavone-enriched extracts of red clover demonstrated neuroprotective effects in human cortical neurons (3) (4) and reduced skin aging in mice by increasing the amount of collagen (5). Clinical trials in humans showed that red clover isoflavone supplementation decreased menopausal symptoms compared to placebo (6) (7) (8). However, conclusions from systematic reviews are conflicting: one suggests marginal benefit whereas the second found no evidence of effectiveness (9) (10). Red clover isoflavones may improve bone loss but more studies are needed (11). In a small study, dietary isoflavone intake improved arterial compliance, an index of the elasticity of large arteries, which is an important cardiovascular risk factor (12).
Red clover was shown to inhibit growth of normal prostate cells and increase resistance of prostate cancer cells to high dose radiation, in vitro (15). Patients should avoid use of red clover during radiotherapy for prostate cancer.
Purported Uses
- Chest congestion
- Menopausal symptoms
- Spasms
Constituents
- Isoflavones: Biochanin, daidzein, formononetin and genistein
- Coumarins: Coumarin and medicagol
- Other constituents: Various flavonoids, saponins, salicylic acid, coumaric acid, minerals, carbohydrates and fats
(14)
Mechanism of Action
Red clover extract stimulates cell proliferation of estrogen receptor positive breast cancer cells in vitro and acts as an estrogen agonist (1). However, Biochinin A, a red clover isoflavone, was shown to inhibit aromatase activity and expression (2), thereby conferring a protective effect. Red clover isoflavones also demonstrated cardioprotective (3) (4) and neuroprotective effects in vitro (12).
Pharmacokinetics
All four isoflavones are metabolized by the liver. Liver demethylation converts biochanin to genistein and formononetin to daidzein. Peak plasma levels of the isoflavones occur within 4-6 hours. Reported serum half-lives of isoflavones range from 9 to 16 hours. Isoflavones are primarily metabolized in either the gut or by the liver to active metabolites.
(13)
Contraindications
- Patients with hormone-sensitive cancers should avoid Red clover because it has estrogenic activity.
- Red clover may increase the effects of anticoagulants and antiplatelet drugs.
Adverse Reactions
- Case report: Subarachnoid hemorrhage was reported in a 53-year-old woman following use of an herbal supplement containing red clover, dong quai, and Siberian ginseng for hot flashes associated with perimenopause. Her symptoms resolved after discontinuing use of the supplement (16).
Herb-Drug Interactions
Anticoagulants / Antiplatelets: Red clover may increase their effects.
Cytochrome P450 enzymes: Red clover can inhibit CYP1A2/2C8/2C9/2C19/2D6 and 3A4, and may interact with substances metabolized by these enzymes (17).
Literature Summary and Critique
Dosage (Inside MSKCC Only)
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References
- Le Bail JC, Champavier Y, Chulia AJ, Habrioux G. Effects of phytoestrogens on aromatase, 3beta and 17beta-hydroxysteroid dehydrogenase activities and human breast cancer cells. Life Sci. 2000;66(14):1281-1291.
- Wang Y, Man Gho W, Chan FL, Chen S, Leung LK. The red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expression. Br J Nutr 2008;99(2):303-310.
- Chen HQ, Jin ZY, Li GH. Biochanin A protects dopaminergic neurons against lipopolysaccharide-induced damage through inhibition of microglia activation and proinflammatory factors generation. Neurosci Lett 2007;417(2):112-117.
- Occhiuto F, Zangla G, Samperi S, et al. The phytoestrogenic isoflavones from Trifolium pratense L. (Red clover) protects human cortical neurons from glutamate toxicity. Phytomedicine 2008.
- Circosta C, De Pasquale R, Palumbo DR, Samperi S, Occhiuto F. Effects of isoflavones from red clover (Trifolium pratense) on skin changes induced by ovariectomy in rats. Phytother Res 2006;20(12):1096-1099.
- Lukaczer D, Darland G, Tripp M, et al. Clinical effects of a proprietary combination isoflavone nutritional supplement in menopausal women: a pilot trial. Altern Ther Health Med 2005;11(5):60-65.
- Hidalgo LA, Chedraui PA, Morocho N, Ross S, San Miguel G. The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: a randomized, double-blind, placebo-controlled study. Gynecol Endocrinol 2005;21(5):257-264.
- van de Weijer PH, Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas 2002;42(3):187-193.
- Coon JT, Pittler MH, Ernst E. Trifolium pratense isoflavones in the treatment of menopausal hot flushes: a systematic review and meta-analysis. Phytomedicine 2007;14(2-3):153-159.
- Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007(4):CD001395.
- Atkinson C, Compston JE, Day NE, Dowsett M, Bingham SA. The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 2004;79(2):326-333.
- Nestel PJ, Pomeroy S, Kay S, et al. Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women. J Clin Endocrinol Metab 1999;84(3):895-898.
- Anon. Promensil. Scientific brochure. North Ryde (Australia): Novogen; 1999.
- Newall C, et al. Herbal Medicines: A Guide for Health-Care Professionals. London: Pharmaceutical Press; 1996.
- Hasan Y, Schoenherr D, Martinez AA, et al. Prostate-specific natural health products (dietary supplements) radiosensitize normal prostate cells. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3):896-904.
- Friedman JA, Taylor SA, McDermott W, Alikhani P. Multifocal and recurrent subarachnoid hemorrhage due to an herbal supplement containing natural coumarins. Neurocrit Care. 2007;7(1):76-80.
- Unger M, Frank A. Simultaneous determination of the inhibitory potency of herbal extracts on the activity of six major cytochrome P450 enzymes using liquid chromatography/mass spectrometry and automated online extraction. Rapid Commun Mass Spectrom. 2004;18(19):2273-81.
Consumer Information
How It Works
Bottom Line: Red clover appears to be ineffective in relieving menopausal symptoms and preventing heart disease in postmenopausal women.
Red clover contains isoflavones, compounds (also found in soy) that have been found to have estrogenic activity in laboratory experiments. The isoflavones in red clover include biochanin, daidzein, formononetin and genistein. However, when used in the body, the effects of red clover isoflavones are less clear. They seem to have estrogenic activity, but so far have not been found to relieve menopausal symptoms or cause the endometrium to grow. A study of menopausal women found that red clover extract improved the elasticity of major arteries. Loss of elasticity has been seen to occur through menopause and it can contribute to increases in blood pressure and extra work on the heart. It is not known if red clover can protect against the development of heart disease; this will require more clinical trials.
In laboratory experiments, red clover extract stimulates the proliferation of estrogen receptor-positive breast cancer cells, indicating that this herb may not be helpful for women with estrogen-sensitive cancers.
Red clover was also shown to inhibit growth of normal prostate cells and increase resistance of prostate cancer cells to high dose radiation, in lab experiments. Patients should avoid use of red clover during radiotherapy for prostate cancer.
Purported Uses
- To relieve chest congestion
No scientific evidence supports this use.
- To relieve the symptoms of menopause
Ared clover product Promensil® was no better than placebo in treating menopausal symptoms.
- To prevent heart disease in post-menopausal women
A few clinical trials have looked at the effects of red clover on development of risk factors for heart disease in post-menopausal women, with no strong evidence that it helps. Most studies found that red clover had no effect on blood cholesterol or triglyceride levels. One clinical trial found that red clover increased the elasticity of major arteries, which may help prevent a gradual rise in blood pressure that can contribute to heart disease.
- To stop muscle spasms
No scientific evidence supports this use.
Research Evidence
A few clinical trials using red clover extracts in menopausal or post-menopausal women found the following:
- Promensil®, a red clover product, was no more effective than placebo in relieving menopausal symptoms.
- Red clover extract was associated with an improvement in elasticity of the major arteries, which may reduce the risk of developing high blood pressure. However, the long-term effects of red clover on risk of heart disease are not known.
- In most clinical trials, red clover had no effect on blood cholesterol or triglyceride levels.
- The effects of red clover on bone mineral density and endometrial growth are still unclear.
Do Not Take If
- You are taking warfarin or other blood thinners (Red clover can increase the risk of bleeding).
- You have a hormone-sensitive disease such as estrogen receptor-positive breast cancer, ovarian cancer, endometriosis, or others (Red clover may have estrogenic activity and should be avoided or used cautiously by patients with these estrogen-sensitive diseases).
Side Effects
- Case report: Intracranial hemorrhage was reported in a 53-year-old woman following use of an herbal supplement containing red clover, dong quai, and Siberian ginseng for hot flashes associated with perimenopause. Her symptoms resolved after discontinuing use of the supplement.
Special Point
- Based on the available evidence, scientists think that red clover has estrogenic effects. There is no proof that red clover is safer than hormone replacement therapy (HRT) in the long-run, since no clinical trials have followed women taking red clover for more than six months.
Last updated: September 28, 2012
biological (BY-oh-LAH-jih-kul)
Pertaining to biology or to life and living things. In medicine, refers to a substance made from a living organism or its products. Biologicals may be used to prevent, diagnose, treat or relieve of symptoms of a disease. For example, antibodies, interleukins, and vaccines are biologicals. Biological also refers to parents and children who are related by blood.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)blood (blud)
A tissue with red blood cells, white blood cells, platelets, and other substances suspended in fluid called plasma. Blood takes oxygen and nutrients to the tissues, and carries away wastes.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)blood pressure (blud PREH-sher)
The force of circulating blood on the walls of the arteries. Blood pressure is taken using two measurements: systolic (measured when the heart beats, when blood pressure is at its highest) and diastolic (measured between heart beats, when blood pressure is at its lowest). Blood pressure is written with the systolic blood pressure first, followed by the diastolic blood pressure (for example 120/80).
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)breast (brest)
Glandular organ located on the chest. The breast is made up of connective tissue, fat, and breast tissue that contains the glands that can make milk. Also called mammary gland.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)cancer (KAN-ser)
A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is a cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is a cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is a cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord. Also called malignancy.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)cardiovascular (KAR-dee-oh-VAS-kyoo-ler)
Having to do with the heart and blood vessels.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)cholesterol (koh-LES-teh-rol)
A waxy, fat-like substance made in the liver, and found in the blood and in all cells of the body. Cholesterol is important for good health and is needed for making cell walls, tissues, hormones, vitamin D, and bile acid. Cholesterol also comes from eating foods taken from animals such as egg yolks, meat, and whole-milk dairy products. Too much cholesterol in the blood may build up in blood vessel walls, block blood flow to tissues and organs, and increase the risk of developing heart disease and stroke.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)clinical (KLIH-nih-kul)
Having to do with the examination and treatment of patients.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)clinical trial (KLIH-nih-kul TRY-ul)
A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical study.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)collagen (KAH-luh-jen)
A fibrous protein found in cartilage and other connective tissue.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)compliance (kum-PLY-unts)
The act of following a medical regimen or schedule correctly and consistently, including taking medicines or following a diet.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)daidzein (DAYD-zine)
An isoflavone found in soy products. Soy isoflavones are being studied in the prevention of cancer.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)dong quai (dong kwye)
An herb native to China. A substance taken from the roots has been used in traditional Chinese medicine to treat menstrual and menopausal problems. Dong quai may increase the effect of the drug warfarin (a blood-thinner). The scientific name is .
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)dose (dose)
The amount of medicine taken, or radiation given, at one time.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)endometrium (en-doh-MEE-tree-um)
The layer of tissue that lines the uterus.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)estrogen (ES-truh-jin)
A type of hormone made by the body that helps develop and maintain female sex characteristics and the growth of long bones. Estrogens can also be made in the laboratory. They may be used as a type of birth control and to treat symptoms of menopause, menstrual disorders, osteoporosis, and other conditions.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)extract (EK-strakt)
In medicine, a preparation of a substance obtained from plants, animals, or bacteria and used as a drug or in drugs.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)genistein (jeh-NIS-teen)
An isoflavone found in soy products. Soy isoflavones are being studied to see if they help prevent cancer.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)ginseng (JIN-seng)
An herb with a root that has been used in some cultures to treat certain medical problems. It may have anticancer effects.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)hemorrhage (HEH-muh-rij)
In medicine, loss of blood from damaged blood vessels. A hemorrhage may be internal or external, and usually involves a lot of bleeding in a short time.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)herbal (ER-bul)
Having to do with plants.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)high blood pressure (hy blud PREH-sher)
A blood pressure of 140/90 or higher. High blood pressure usually has no symptoms. It can harm the arteries and cause an increase in the risk of stroke, heart attack, kidney failure, and blindness. Also called hypertension.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)hormone (HOR-mone)
One of many chemicals made by glands in the body. Hormones circulate in the bloodstream and control the actions of certain cells or organs. Some hormones can also be made in the laboratory.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)in vitro (in VEE-troh)
In the laboratory (outside the body). The opposite of in vivo (in the body).
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)isoflavone (I-soh-FLAY-vone)
An estrogen-like substance made by some plants, including the soy plant. Soy isoflavones are being studied in the prevention of cancer, hot flashes that occur with menopause, and osteoporosis (loss of bone density).
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)menopause (MEH-nuh-pawz)
The time of life when a woman’s ovaries stop producing hormones and menstrual periods stop. Natural menopause usually occurs around age 50. A woman is said to be in menopause when she hasn’t had a period for 12 months in a row. Symptoms of menopause include hot flashes, mood swings, night sweats, vaginal dryness, trouble concentrating, and infertility.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)placebo (pluh-SEE-boh)
An inactive substance or treatment that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)placebo-controlled (pluh-SEE-boh-kun-TROLD)
Refers to a clinical study in which the control patients receive a placebo.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)postmenopausal (post-MEH-nuh-PAW-zul)
Having to do with the time after menopause. Menopause (“change of life”) is the time in a woman's life when menstrual periods stop permanently.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)prostate (PROS-tayt)
A gland in the male reproductive system. The prostate surrounds the part of the urethra (the tube that empties the bladder) just below the bladder, and produces a fluid that forms part of the semen.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)prostate cancer (PROS-tayt KAN-ser)
Cancer that forms in tissues of the prostate (a gland in the male reproductive system found below the bladder and in front of the rectum). Prostate cancer usually occurs in older men.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)radiation (RAY-dee-AY-shun)
Energy released in the form of particle or electromagnetic waves. Common sources of radiation include radon gas, cosmic rays from outer space, medical x-rays, and energy given off by a radioisotope (unstable form of a chemical element that releases radiation as it breaks down and becomes more stable).
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)radiotherapy (RAY-dee-oh-THAYR-uh-pee)
The use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body near cancer cells (internal radiation therapy). Systemic radiotherapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that travels in the blood to tissues throughout the body. Also called irradiation and radiation therapy.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)randomized
Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments.
(http://www.cancer.gov/dictionary)red clover (red KLOH-ver)
Trifolium pratense. A plant with flowers that has been used in some cultures to treat certain medical problems. It is being studied in the relief of menopausal symptoms and may have anticancer effects. Also called purple clover, Trifolium pratense, and wild clover.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)reduction (ree-DUK-shun)
A chemical reaction that takes place when a substance comes into contact with hydrogen or another reducing substance.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)resistance
Failure of a cancer to shrink after treatment.
(http://www.cancer.gov/dictionary)risk factor (... FAK-ter)
Something that increases the chance of developing a disease. Some examples of risk factors for cancer are age, a family history of certain cancers, use of tobacco products, being exposed to radiation or certain chemicals, infection with certain viruses or bacteria, and certain genetic changes.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)significant (sig-NIH-fih-kunt)
In statistics, describes a mathematical measure of difference between groups. The difference is said to be significant if it is greater than what might be expected to happen by chance alone. Also called statistically significant.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)supplementation (SUH-pleh-men-TAY-shun)
Adding nutrients to the diet.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)therapy (THAYR-uh-pee)
Treatment.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)will (wil)
A legal document in which a person states what is to be done with his or her property after death, who is to carry out the terms of the will, and who is to care for any minor children.
Source: The National Cancer Institute's Dictionary of Cancer Terms
(http://www.cancer.gov/dictionary)
