Written by Sarah Vadeboncoeur and the CAM-Cancer Consortium.
Updated February 8, 2017

Red clover (Trifolium pratense)

What is it?

Description

Red clover is a legume in the Fabaceae family that is indigenous to Europe and parts of the Middle East and has been naturalized to North America1.

Scientific Names/Brand Names

Trifolium pratense. Red clover products include Promensil®, Rimostil®, Menoflavon®, and Estrofactors®.

Ingredients

Red clover contains flavonoids, coumarins2, isoflavones and is especially high in coumestans. Red clover contains at least 9 isoflavones3 including formononetin and biochanin A (glycosides), and daidzein and genistein (aglycones)1.

Application and dosage

Red clover is most commonly taken orally but can also be used topically. The recommended daily dose of red clover extracts ranges from 40 to 80 mg daily4.

History

For centuries, red clover has been grown in pastures to feed cattle and other grazing animals. Humans have rarely consumed red clover in their diets, although it has a long history of medicinal uses.

Claims of efficacy/alleged indications

Traditionally, red clover has been used for a variety of health conditions. Currently, it is commonly used in the treatment of hot flushes, osteoporosis, and cardiovascular disease. In oncology, it has been claimed to be effective for treating hormonally driven cancers (breast, ovarian, uterine) and for reducing hot flushes in women who experience premature menopause as part of their cancer treatment5. Topically, red clover is used for cancer, burns, and chronic skin diseases including eczema and psoriasis.

Mechanism of action

Red clover has been shown to function as both an oestrogen receptor agonist1 and antagonist, depending on the state of its metabolites 36. Red clover metabolites exhibit a highest affinity for beta-estrogens receptors yet weak binding affinity for androgen and progesterone receptors6. Its anti-neoplastic effects may be attributed to effects on the cell cycle and apoptosis7 and COX-8 and angiogenesis inhibition9.

Prevalence of use

Increasingly, many women are turning to phytooestrogens as an alternative to hormone replacement therapies because of their adverse effects. Precise prevalence figures are unavailable; however, one study reported that 39.5% of 767 breast cancer survivors were using estrogenic botanical supplements10.

Legal issues

Red clover is sold as a natural health product or herbal dietary supplement in North America and Europe.

Cost and expenditure

An average daily cost of the red clover supplements such as Promensil is €0.70, US$ 1.00 and CDN $1.25.

Citation Sarah Vadeboncoeur, CAM-Cancer Consortium. Red clover (Trifolium pratense) [online document]. http://ws.cam-cancer.org/The-Summaries/Herbal-products/Red-clover-Trifolium-pratense. February 8, 2017.

References

  1. Osoki L, Kennelly E. Phytoestrogens: A Review of the Present State of Research. Phytother. Res. 2003; 17: 845–869
  2. Cheema D, Coomarasamy A, El-Toukhy T. Non-hormonal therapy of post-menopausal vasomotor symptoms: a structured evidence-based review. Arch Gynecol Obstet, 2007 ; 276:463–469.
  3. Maul R & Kulling S. Absorption of red clover isoflavones in human subjects: results from a pilot study. British Journal of Medicine. 2010;103(11):1569-72.
  4. Fugate SE, Church CO Nonestrogen Treatment Modalities for Vasomotor Symptoms Associated with Menopause. The Annals of Pharmacotherapy. 2004; 38:1482-99.
  5. Natural Medicine Comprehensive Database [Online]. Red Clover. Available from https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=308 [Accessed 8 February 2017]
  6. Bodinet C, Freudenstein J. Influence of marketed herbal menopause preparations on MCF-7 cell proliferation. Menopause. 2004; 11( 3):281-289.
  7. Medjakovic S, Jungbauer A. Red clover isoflavones biochanin A and formononetin are potent liagands of the human aryl hydrocarbon receptor. Journal of Steroid Biochemistry & Molecular Biology. 2008;108:171-177.
  8. Lam A, Demasi M, James M, Husband A, Walker C. Effect of Red Clover Isoflavones on Cox-2 Activity in Murine and Human Monocye/Macrohpage Cells. Nutrition and Cancer. 2004;49(1):89-93.
  9. Kreen L & Paper DH. Inhibition of Angiogenesis and Inflammation by an extract of red clover (Trifolium pratense L.) Phytomedicine. 2009;16:1083-88.
  10. Ma H, Sullivan-Halley J, Smith A, Neuhouser M, Alfano C, Meeske K, George S, McTiernan A, McKean-Cowdin R, Baumgartner K, Ballard-Barbash R, Bernstein L. Estrogenic Botanical Supplements, health related quality of life, and hormone related symptoms in breast cancer survivors: a HEAL study report. BMC Complementary and Alternative Medicine. 2011;11:109.
  11. Hooper L, Madhavan G, Tice J, Leinster S, Cassidy A. Effects of Isoflavones on breast density in pre- and post-menopausal women: a systematic review and meta-analysis of randomized control trials. Human Reproduction Update. 2010;16(6):745-760.
  12. Tempfer C, Bentz E-K, Leodolter, S, Tcsherne G, Reuss F, Cross H, Huber J. Phytoestrogens in Clinical Practice: a review of the literature. Fertil Steril. 2007; 87: 1243-9.
  13. Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007;(4): CD001395.
  14. Thompson Coon J, Pittler M, Ernst E. Trifolium pratense isoflavones in the treatment of menopausal hot flushes: A systematic review and meta-analysis. Phytomedicine. 2006; 14:153-159.
  15. Booth N, Piersen C, Banuvar S, Geller S, Shulman L, Farnsworth, N. Clinical studies of red clover (Trifolium pratense) dietary supplements in menopause: a literature review. Menopause: Journal of the North American Menopause Society. 2006; 13(2):251-264.
  16. Hale G, Hughes C, Robboy S, Agarwal S, Bievre M. A double-blind randomized study on the effects of red clover isoflavones on the endometrium. Menopause: The Journal of the North American Menopause Society. 2011;8(5):338-346.
  17. Song W, Chun OK, Hwang I, Shin HS, Kim B-G, Kim KS, Lee S-Y, Shin D, Lee S. Soy Isoflavones as safe functional ingredients. Journal of Medicinal Food. 2007; 10(4): 571-580.
  18. Atkinson C, Warren R, Sala E, Dowsett M, Dunning A, Healey C, Runswick S, Day N, Bingham S. Red clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial. Breast Cancer Research. 2004; 6(3): R1 70-79.
  19. Vrieling A, Rookus M, Kampman E, Bonfrer J, Korse C, van Doorn J, Lampe J, Cats A, Witteman B, van Leeuwen F, van’t Veer L, Voskuil D. Isolated Isoflavones Do Not Affect the Circulating Insulin-Like Growth Factor System in Men at Increased Colorectal Cancer Risk. The Journal of Nutrition. 2007; 137:379-383.
  20. Jarred R, Keikha M, Dowling C et al. Induction of Apoptosis in Low to Moderate-Grade Human Prostate Carcinoma by Red-Clover Derived Dietary Isoflavones. Cancer Epidemiology, Biomarkers & Prevention. 2002;11:1689-96.
  21. Stephens, F. Phytoestrogens and prostate cancer: possible preventive role. Medical Journal of Australia. 1997; 167: 138-40.
  22. Chan H, Wang H, Leung L. The red clover (Trifolium pratense) isoflavone biochanin A modulates the biotransformation pathways of 7,12-dimethylbenz[a]anthracene. British Journal of Nutrition. 2003;90(1):87-92.
  23. Han E, Kim J & Jeong H. Effect of Biochanin A on the Aryl Hydrocarbon Receptor and Cytochrome P450 1A1 in MCF-7 Human Breast Carcinoma Cells. Arch Pharm Res. 2006;29(7):570-576.
  24. Boué S, Wiese T, Nehls S, Burow M, Elliott S, Carter-Wientjes C, Shih B, McLachlan J, Cleveland T. Evaluation of the Estrogenic Effects of Legume Extracts Containing Phytoestrogens. Journal of Agricultural and Food Chemistry. 2003;51:2193-2199.
  25. Fokialakis N, Alexi X, Aligiannis N, Siriani D, Meligova A, Pratsinis H, Mitakou S, Alexis M. Ester and carbamate ester derivatives of Biochanin A: Synthesis and in vitro evaluation of estrogenic and antiproliferative activities. Bioorganic & Medicinal Chemistry. 2012;20:2962-2970.
  26. Rice L, Samedi V, Medrano T, Sweeney C, Baker H, Stenstrom A, Furman J, Shiverick K. Mechanism of Growth Inhibitory Effects of the Isoflavonoid Biochanin A on LNCaP Cells and Xenografts. The Prostate. 2002;52:201-212.
  27. Szliszka E, Czuba Z, Mertas MD, Paradysz A, Krol W. The dietary isoflavone biochanin-A sensitizes prostate cancer cells to TRAIL-induced apoptosis. Urologic Oncology. 2011.
  28. Wang Y, Gho WM, Chan F, Chen S, Leung L. The red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expression. British Journal of Nutrition. 2008;99(2):303-310.
  29. Liu J, Burdette J, Xu H, Chungang G, van Breernen R, Bhat K, Booth N, Constantinou A, Pezzuto J, Fong H, Farnsworth N, Bolton J. Evaluation of Estrogenic Activity of Plant Extracts for the Potential Treatment of Menopausal Symptoms. J. Agric Food Chem. 2001; 49:2472-79.
  30. Jarred R, McPherson S, Jones M, Simpson E, Risbridger G. Anti-Androgenic Action by Red Clover-Derived Deitary Isoflavones reduces Non-Malignant Prostate Enlargement in Aromatase Knockout (ArKO) Mice. The Prostate. 2003;56:54-64.
  31. Gray N, Liu X, Choi R et al. Endocrine-Immune Paracrine Interactions in Prostate Cells as Targeted by Phytomedicines. Cancer Prev Res. 2009;2:134-42.
  32. Liu X, Piao Y, Arnold J. Transforming gowth factor B1 increase of hydroxysteroid dehydrogenase proteins is partly suppressed by red clover isoflavones in human primary prostate cancer-derived stromal cells. Carcinogenesis. 2011;32(11):1648-54.
  33. Booth N, Overk C, Yao P, Totura S, Deng Y, Hedayat AS, Bolton J, Pauli G, Farnsworth N. Seasonal Variation of Red Clover (Trifolium pratense L., Fabaceae) Isoflavones and Estrogenic Activity. Journal of Agricultural and Food Chemistry. 2006;54:1277-82.
  34. Roberts H. Safety of herbal medicinal products in women with breast cancer. Maturitas. 2010; 66:363-369.Moyad M. Complementary/Alternative Therapies for reducing hot flashes in prostate cancer patients: re-evaluating the existing indirect data from studies of breast cancer and postmenopausal women. Urology. 2002; 59(Supplement 4A):20-33.
  35. Moyad M. Complementary/Alternative Therapies for reducing hot flashes in prostate cancer patients: re-evaluating the existing indirect data from studies of breast cancer and postmenopausal women. Urology. 2002; 59(Supplement 4A):20-33.
  36. Pfitscher A, Reiter E, Jungbauer A. Receptor binding and transactivation activities of red clover isoflavones and their metabolites. J Steroid Biochem Mol Biol 2008 Nov;112(1-3):87-94)