Health Care Professional Information

Scientific Name
Trifolium pratense
Common Name

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

Brand Name

Promensil®, Rimonstil®

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 data show that red clover isoflavone supplementation improves 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).
In postmenopausal women, red clover supplements were shown to alleviate vasomotor and menopausal symptoms (18).
Red clover isoflavones may also improve bone loss but more data 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
  • Volatile Oils: Alcohols, aldehydes, ketones, terpenes, esters, hydrocarbons, phenolics and acids
    (13) (14)
Mechanism of Action

Formononetin, a red clover isoflavone, induced apoptosis in human breast cancer cells by activating the Ras-p38 mitogen-activated protein kinase in ER-positive breast cancer cells (23).
Biochanin A, another red clover isoflavone had inhibitory effects on the activity and gene expression of aromatase, an enzyme that catalyzes the conversion of androgen to estrogen (2). It also protected dopaminergic neurons against lipopolysaccharide-induced damage via inhibition of microglial activation and generation of pro-inflammatory factors (3).
An isoflavone-enriched fraction too showed neuroprotective activity in human cortical neurons, which is thought to be due to antioxidant and estrogenic effects (4).
In a study of rats, red clover isoflavones reduced skin aging induced by estrogen deprivation following ovariectomy (5).

Pharmacokinetics

After consumption of a low-isoflavone diet for 2 weeks, followed by an oral dose of two isoflavone tablets (80 mg of total isoflavones) daily for 2 weeks, plasma samples were collected for a 48-hour period after the last dose from fourteen subjects.
Genistein and daidzein have sufficiently long plasma half-lives in humans during long term administration to allow once daily administration of isoflavone supplements containing biochanin, formononetin, genistein, and daidzein. Biochannin and formonetin are rapidly and extensively metabolised to genestein and daidzein (22).

Contraindications
  • Patients with hormone-sensitive cancers should avoid red clover because it has estrogenic activity(21).
  • Red clover may increase the effects of anticoagulants and antiplatelet drugs (20).
  • Red clover causes toxic effects when used with methotrexate (19).
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 (20).
Cytochrome P450 enzymes: Red clover can inhibit CYP1A2/2C8/2C9/2C19/2D6 and 3A4, and may interact with substances metabolized by these enzymes (17).
Methotrexate: Red clover has been reported to cause toxicity, resulting in severe vomiting and epigastric pain, when used along with methotrexate injections (19).

Literature Summary and Critique

Lipovac M, Chedraui P, Gruenhut C, et al. The effect of red clover isoflavone supplementation over vasomotor and menopausal symptoms in postmenopausal women. Gynecol Endocrinol. 2012 Mar;28(3):203-7.
In this study, 109 postmenopausal women aged 40 or more were randomized to receive two daily capsules of the active compound (80 mg red clover isoflavones, Group A) or a placebo (Group B) for 90 days. Following a washout period of 7 days, the medication and placebo was crossed over and administered for 90 more days. The frequency of daily hot flushes and night sweats, and overall menopausal symptom intensity (Kupperman Index) were measured at baseline, 90, 97 and 187 days. Researchers report that the KI values were similar in both studied groups at baseline, but decreased significantly after red clover treatment in Group A. And after washout and placebo phases, there was a significant rise in the values. In Group B, all indices remained the same after placebo and washout phases, but decreased significantly after red clover treatment. No side effects were reported with red clover.
Supplementation with red clover isoflavones may help to reduce vasomotor symptoms and overall menopausal intensity in postmenopausal women.

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 involving 252 postmenopausal women. The participants were randomly assigned to take isoflavone clover extract from 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 after 12 weeks was similar in all three groups. The authors concluded that even though Promensil ® has biological effect, it does not have a significant effect on menopausal symptoms including hot flashes.

Dosage (Inside MSKCC Only)
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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. Brandli A, Simpson JS, Ventura S. Isoflavones isolated from red clover (Trifolium pratense) inhibit smooth muscle contraction of the isolated rat prostate gland. Phytomedicine. 2010 Sep;17(11):895-901.
  14. Tava A, Ramella D, Grecchi M, et al.Volatile constituents of Trifolium pratense and T. repens from N.E. Italian alpine pastures. Nat Prod Commun. 2009 Jun;4(6):835-8.
  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.
  18. Lipovac M, Chedraui P, Gruenhut C, et al. The effect of red clover isoflavone supplementation over vasomotor and menopausal symptoms in postmenopausal women. Gynecol Endocrinol. 2012 Mar;28(3):203-7.
  19. Orr A, Parker R. Red clover causing symptoms suggestive of methotrexate toxicity in a patient on high-dose methotrexate. Menopause Int. 2013 Sep;19(3):133-4.
  20. Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm. 2000 Jul 1;57(13):1221-7.
  21. Booth NL, Overk CR, Yao P, et al. The chemical and biologic profile of a red clover (Trifolium pratense L.) phase II clinical extract. J Altern Complement Med. 2006 Mar;12(2):133-9.
  22. Howes J, Waring M, Huang L, Howes LG. Long-term pharmacokinetics of an extract of isoflavones from red clover (Trifolium pratense). J Altern Complement Med. 2002 Apr;8(2):135-42.
  23. Chen J, Sun L. Formononetin-induced apoptosis by activation of Ras/p38 mitogen-activated protein kinase in estrogen receptor-positive human breast cancer cells. Horm Metab Res. 2012 Dec;44(13):943-8.

Consumer Information

How It Works

Bottom Line: Red clover may help reduce some menopausal symptoms.

Red clover contains compounds known as isoflavones (also found in soy) that show 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 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

Menopausal Symptoms
In this study, 109 postmenopausal women aged 40 or more received two daily capsules (80 mg red clover isoflavones, Group A) or a placebo (Group B) for 90 days. Following a washout period of 7 days, the medication and placebo was crossed over and taken for 90 more days. The frequency of daily hot flushes and night sweats, and overall menopausal symptom intensity were measured. Researchers found that the KI values were similar in both studied groups at baseline, but decreased significantly after red clover treatment in Group A. And after washout and placebo phases, there was a significant rise in the values. In Group B, all values remained the same after placebo and washout phases, but decreased significantly after red clover treatment. No side effects were reported with red clover.
Supplementation with red clover isoflavones may help to reduce vasomotor symptoms and overall menopausal intensity in postmenopausal women.

In a large, multicenter, randomized, placebo-controlled trial of red clover extract, 252 postmenopausal women received an isoflavone clover extract from Promensil ®, Rimostil ® or a 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 decrease in hot flashes after 12 weeks was similar in all three groups. Promensil ® does not have a significant effect on hot flashes.

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).
  • You are taking methotrexate (red clover may cause toxic effects, including severe vomiting and pain in the upper abdomen).
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.
E-mail your questions and comments to aboutherbs@mskcc.org.