Description
Red clover (Trifolium pratense) is a medicinal herb containing flavonoids, coumarins, coumestans, and isoflavones that can be taken orally or applied topically. Red clover has been claimed to be effective for the treatment of hot flushes, osteoporosis, and cardiovascular disease. In oncology, it has been claimed to be effective for treating hormonally driven cancers and for reducing hot flushes in women who experience premature menopause as part of their cancer treatment.
Efficacy
Breast and ovarian cancers: The current evidence for its use in women with breast and ovarian cancers based on one systematic review and one additional trial is insufficient.
Hot flushes: Evidence is lacking for the use of red clover in women with cancer experiencing hot flushes, and the majority of clinical trials conducted among women without cancer have found that red clover is no more effective than placebo in reducing hot flushes. A single observational study among breast cancer survivors found that women using red clover supplements were less likely to report night sweats.
Prostate and colon cancers: Preliminary studies suggest that red clover isoflavones may be of benefit in prostate and colon cancers but the evidence is not sufficient.
Safety
Although red clover is generally well tolerated by women without cancer, drug-nutrient and nutrient-nutrient interactions are theoretically possible. Safety data is lacking in women with cancer.
Citation
Sarah Vadeboncoeur, CAM Cancer Collaboration. Red clover (Trifolium pratense) [online document], Jan 8, 2019
Document history
Assessed as up to date in January 2019 by Barbara Wider.
Assessed as up to date in February 2017 by Barbara Wider.
Assessed as up to date in January 2015 by Barbara Wider.
Summary first published in February 2013 by Sarah Vadeboncoeur.
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 metabolites36. 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.
Description of included studies
Based on the current available evidence, red clover’s efficacy in the treatment of breast, uterine, colon, and prostate cancers is uncertain.
Breast cancer
A meta-analysis of 8 RCTs, including 1287 breast cancer survivors, suggested that isoflavones had no significant effect on breast density among post-menopausal women but there may be a small increase in breast density among pre-menopausal women. The data did not evaluate the effects of red clover alone, but the authors conclude that the available evidence suggests that there is no differential effect based on isoflavone source11. There is a moderate risk of bias in the studies included and the data was deemed insufficient to directly assess the effects of isoflavones on breast cancer or mortality.
The HEAL prospective study conducted among 767 breast cancer survivors found that women using red clover supplements were less likely to report night sweats but there was no effect on hot flushes or quality of life10. The generalisability of this trial is limited as it included only 38 red clover users.
No additional clinical trials were identified that directly evaluate the effects of red clover isoflavone supplementation in women with breast cancer. One clinical trial among women with an increased risk of breast cancer found that one year of red clover supplementation had no effect on steroid hormone levels compared with placebo15. Red clover’s protective effects in cancer prevention have not yet been demonstrated in clinical studies.
Hot flushes
There are no meta-analyses or controlled clinical trials of the effects of red clover on hot flushes in women with cancer. However, three meta-analyses and systematic reviews have been conducted in women without cancer. Two found that red clover is no more effective than placebo in reducing hot flush frequency12,13 while another reported evidence of a marginally significant effect of red clover on hot flush frequency in menopausal women14. Due to the heterogeneity and limited number of studies included, it is unclear whether the effect is clinical significant.
Uterine cancer
Three clinical trials examined the effects of red clover supplementation on the development of uterine cancer. Red clover supplementation did not affect the proliferative index of endometrial biopsies16, endometrial thickness17, or breakthrough bleeding compared with placebo18.
Colorectal cancer
A 2-month crossover RCT using 84 mg of red clover daily was conducted among 37 men at high risk for colorectal cancer. It found that red clover isoflavone supplementation did not influence serum insulin-like growth factor (IGF-1). However, decreased total IGF-1 concentrations were associated with increased serum equol concentrations, suggesting that isoflavones may lower IGF-1 only among equol producers19.
Prostate cancer
A case-controlled study among 38 men with prostate cancer who received 160 mg of red clover isoflavones found an increase in apoptosis in regions of low- to moderate-grade cancer but no differences in PSA, Gleason score, and serum testosterone20. A case report of a 66 year old male with high-grade adenocarcinoma who, of his own initiative, took 160 mg of red clover phytoestrogens (Promensil) daily for the 7 days leading up to his prostatectomy also reported that his prostatectomy specimen revealed histological changes consistent with tumour regression21.
Pre-clinical studies
Animal and in-vitro studies indicate that red clover isoflavones exert their action by activating both estrogen22 and progesterone receptors23. Results of pre-clinical studies are mixed as red clover has been found to both activate17 and inhibit24,25 the proliferation of breast cancer cells. Preliminary results suggest that it may also inhibit endometrial24 and prostate cancer cells26. Red clover’s anti-neoplastic properties are believed to result from protection against DNA damage22,23, cytotoxic effects, inducing apoptosis27, inhibiting aromatase28, and modulating steroid hormone levels29-32.
It has been suggested that the seasonal variation of red clover isoflavones may in part be responsible for the conflicting findings about red clover’s effects33.
Safety data in women with cancer is generally lacking; the information below refers to women without cancer.
Adverse events
Red clover is generally well tolerated but has been reported to cause minor adverse effects, some occurring at doses as low as 40 mg per day. Adverse effects include: headaches, myalgia, arthralgia, nausea, and diarrhoea2, breast tenderness, swollen neck glands, dizziness, vertigo, tremor, hypertension, acne, rash, pruritis, psoriasis, bloating, constipation, mouth ulcer, sore throat, osteoarthritis, bronchitis, low platelets, reflux, epistaxis, menstrual bleeding, urinary tract infection, and vaginal thrush. Compounds and mechanisms responsible for triggering adverse events are currently unknown33. A large trial of a red clover extract (Promensil) versus placebo reported no differences in the proportion of women who experienced any adverse events and no differences in the rate of specific adverse events between groups33.
Interactions
There are no reports of clinically significant drug interactions with red clover in the published literature. Red clover isoflavones can inhibit CYP IA1, CYP IBI and CYP 2C9 metabolic liver enzymes and may increase plasma levels of drugs metabolised through these pathways34.
Use of red clover concomitantly with herbs that have constituents that might affect platelet aggregation could theoretically increase the risk of bleeding in some people. These herbs include angelica, clove, danshen, garlic, ginger, ginkgo, Panax ginseng, horse chestnut, turmeric, and others5.
Use of red clover with oestrogenic herbs and drugs, including tamoxifen, are theoretically contraindicated as red clover may have additive or antagonistic effects5.
Contraindications
Some suggest testing prothrombin time and/or partial thromboplastin time prior to initiating therapy34 and avoiding its use in those with bleeding disorders2. Individuals with thyroid conditions should use caution when consuming phytooestrogens as one animal study reported higher concentrations of some thyroid hormones with red clover use1. Red clover is contraindicated during pregnancy33.
Contamination issues
There are some concerns about the potential presence of coumarins in some products or specific species of red clover which can affect bleeding time. It is therefore contraindicated in those with bleeding disorders.
Osoki L, Kennelly E. Phytoestrogens: A Review of the Present State of Research. Phytother. Res. 2003; 17: 845–869
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.
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.
Fugate SE, Church CO Nonestrogen Treatment Modalities for Vasomotor Symptoms Associated with Menopause. The Annals of Pharmacotherapy. 2004; 38:1482-99.
Natural Medicine Comprehensive Database. Red Clover. Available online.[Accessed 8 February 2017]
Bodinet C, Freudenstein J. Influence of marketed herbal menopause preparations on MCF-7 cell proliferation. Menopause. 2004; 11( 3):281-289.
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.
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.
Krenn L & Paper DH. Inhibition of Angiogenesis and Inflammation by an extract of red clover (Trifolium pratense L.) Phytomedicine. 2009;16:1083-88.
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.
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.
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.
Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007;(4): CD001395.
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.
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.
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.
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.
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.
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.
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.
Stephens, F. Phytoestrogens and prostate cancer: possible preventive role. Medical Journal of Australia. 1997; 167: 138-40.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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)
