About Herbs, Botanicals & Other Products

Scientific Name
Trifolium pratense
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Common Name

Cow clover, Wild clover, Purple clover Beebread, Cow grass, Meadow clover, Purple clover

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Brand Name

Promensil®, Rimonstil®

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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.

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Purported Uses
  • Chest congestion
  • Menopausal symptoms
  • Spasms
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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)
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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).

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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)

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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.
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Adverse Reactions
  • Case report: Subarachnoid hemorrhage was reported in a 53-year-old woman following use of a 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).
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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).

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Literature Summary and Critique

Tice J, et al. Phytoestrogen Supplements for the Treatment of Hot Flashes: The Isoflavone Clover Extract (ICE) Study: A Randomized Controlled Trial. JAMA 2003 Jul 9;290(2):207-14.
This was a large, multicenter, randomized, placebo-controlled trial of red clover extract. 252 postmenopausal women were randomly assigned to take isoflavone clover extract from either Promensil ®, Rimostil ® or an identical placebo daily for 12 weeks. Promensil ®, but not Rimonstil ®, was shown to reduce hot flashes at a faster rate than placebo during this period. However, the reduction of hot flashes counts after 12 weeks were similar in all three groups. The authors concluded that even though Promensil ® has biological effect, it does not have a signficant effect on menopausal symptoms including hot flashes.

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References
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007(4):CD001395.
  11. 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.
  12. 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.
  13. Anon. Promensil. Scientific brochure. North Ryde (Australia): Novogen; 1999.
  14. Newall C, et al. Herbal Medicines: A Guide for Health-Care Professionals. London: Pharmaceutical Press; 1996.
  15. 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.
  16. 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.
  17. 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.
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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.

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Purported Uses
  • To relieve chest congestion
    No scientific evidence supports this use.
  • To relieve the symptoms of menopause
    Some studies show that red clover has an estrogenic effect. The red clover product Promensil® was found to be no better than placebo in treating menopausal symptoms except it can reduce hot flashes more rapidly.
  • To prevent heart disease in post-menopausal women
    A handful of clinical trials have looked at the the effects of red clover on development of risk factors for heart disease in post-menopausal women, with no strong evidence that it helps. Almost all of the clinical trials 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.
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Research Evidence

A few clinical trials using red clover extracts in menopausal or post-menopausal women found that

  • 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 almost all of the 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.
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Patient Warnings
  • This product is regulated by the FDA as a dietary supplement. Unlike approved drugs, supplements are not required to be manufactured under specific standardized conditions. This product may not contain the labeled amount or may be contaminated. In addition, it may not have been tested for safety or effectiveness.
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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).
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Side Effects
  • Case report: Intracranial hemorrhage was reported in a 53-year-old woman following use of a 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.
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Special Point
  • Based on the available evidence, scientists think that red clover has estrogenic effects. There is no proof that red clover is any more safe than hormone replacement therapy (HRT) in the long-run, since no clinical trials have followed women taking red clover for more than six months.
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Dosage (Inside MSKCC Only)
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Aliases
Promensil®
Trifolium Pratense
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E-mail your questions and comments to aboutherbs@mskcc.org.
Last updated: February 17, 2011