The use of dietary supplements by patients with cancer has increased significantly over the past 2 decades despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information.
The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on integrative and complementary therapies commonly used by patients with cancer. We chose red clover for this issue because of its popularity among breast cancer patients.
Compiled by Barrie R. Cassileth, MS, PhD, and Jyothi Gubili, MS, Memorial Sloan Kettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, MBA, LAc, Memorial Sloan Kettering Cancer Center.
Red Clover
Scientific name: Trifolium pratense
Common names: Cow clover, wild clover, purple clover, beebread, cow grass, meadow clover
Overview
Red clover is a perennial herb that commonly grows in meadows in Asia and Europe, and is now prevalent in North America as well. It produces dark pink flowers in thick inflorescences that are used in herbal medicine.
Red clover has been used in traditional medicine to treat skin disorders such as psoriasis and eczema, cough, and mastitis. It was also valued as a blood purifier and used as a folk treatment for cancer. It is an ingredient in some “alternative” (nonviable) cancer treatments such as Hoxsey therapy.
It was the identification of phytoestrogenic isoflavones that made red clover popular as an alternative to hormonal therapy for the relief of menopausal symptoms. However, clinical data on red clover’s ability to alleviate menopausal symptoms are inconclusive.
Red clover is available in the form of teas, tinctures, tablets, and capsules, as an ointment for topical application, and as extracts standardized to specific isoflavones. Two heavily promoted extracts include Promensil, for the treatment of menopausal symptoms, and Trinovin, for prostate health.
Patients with breast cancer should avoid red clover because it may stimulate proliferation of estrogen receptor (ER)-positive breast cancer cells.
The Science
Red clover extract acts as an estrogen agonist and stimulates proliferation of ER-positive breast cancer cells in vitro.1 However, biochinin A, a red clover isoflavone, inhibits aromatase activity and expression,2 and may confer a protective effect.
Isoflavone-enriched red clover extracts also demonstrated neuroprotective effects in human cortical neurons,3,4 and by increasing collagen content, red clover reduced skin aging in mice.5
Clinical data indicate that red clover isoflavone supplementation improves menopausal symptoms.6-8 But analyses of systematic reviews conflict: One suggests a small benefit; the second found no evidence of effectiveness.9,10 In a study of postmenopausal women, red clover supplements alleviated vasomotor and menopausal symptoms.11
Red clover isoflavones may reduce bone loss12 and improve arterial compliance, an index of the elasticity of large arteries, an important risk factor for cardiovascular disease.13 However, red clover was shown to increase resistance of prostate cancer cells to high dose radiation, and prevent the growth of normal prostate cells.14
In summary, red clover appears useful in alleviating menopausal symptoms, but there are no data to support its anticancer effects.
Adverse Effects
Case report: A 53-year-old woman suffered subarachnoid hemorrhage after taking an herbal supplement (containing red clover, dong quai, and Siberian ginseng) for hot flashes associated with perimenopause. Her symptoms resolved following discontinuation of supplement use.15
Herb-Drug Interactions
Anticoagulants/antiplatelets: Red clover may enhance their effects.16
Cytochrome P450 enzymes: Red clover inhibits CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4, and may interact with substances metabolized by these enzymes.17
Methotrexate: Concurrent use of red clover with methotrexate injections resulted in severe vomiting and epigastric pain.18 ■
Disclosure: Ms. Gubili reported no potential conflicts of interest.
References
1. Le Bail JC, Champavier Y, Chulia AJ, et al: Effects of phytoestrogens on aromatase, 3beta and 17beta-hydroxysteroid dehydrogenase activities and human breast cancer cells. Life Sci 66:1281-1291, 2000.
2. Wang Y, Man Gho W, Chan FL, et al: The red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expression. Br J Nutr 99:303-310, 2008.
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 417:112-117, 2007.
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 15:676-682, 2008.
5. Circosta C, De Pasquale R, Palumbo DR, et al: Effects of isoflavones from red clover (Trifolium pratense) on skin changes induced by ovariectomy in rats. Phytother Res 20:1096-1099, 2006.
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 11:60-65, 2005.
7. Hidalgo LA, Chedraui PA, Morocho N, et al: 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 21:257-264, 2005.
8. van de Weijer PH, Barentsen R: Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas 42:187-193, 2002.
9. Coon JT, Pittler MH, Ernst E: Trifolium pratense isoflavones in the treatment of menopausal hot flushes: A systematic review and meta-analysis. Phytomedicine 14:153-159, 2007.
10. Lethaby AE, Brown J, Marjoribanks J, et al: Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev (4):CD001395, 2007.
11. 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 28:203-207, 2012.
12. Atkinson C, Compston JE, Day NE, et al: The effects of phytoestrogen isoflavones on bone density in women: A double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 79:326-333, 2004.
13. 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 84:895-898, 1999.
14. 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 76:896-904, 2010.
15. Friedman JA, Taylor SA, McDermott W, et al: Multifocal and recurrent subarachnoid hemorrhage due to an herbal supplement containing natural coumarins. Neurocrit Care 7:76-80, 2007.
16. Heck AM, DeWitt BA, Lukes AL: Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm 57:1221-1227, 2000.
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 18:2273-2281, 2004.
18. Orr A, Parker R: Red clover causing symptoms suggestive of methotrexate toxicity in a patient on high-dose methotrexate. Menopause Int 19:133-134, 2013.
Jyothirmai Gubili, MS, is Editor, Integrative Medicine Service at Memorial Sloan Kettering Cancer Center.
Integrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York.
The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and maintains a free website—About Herbs (www.mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the close to 300 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings.
In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, can be downloaded at http://itunes.apple.com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices.
