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

Red clover (Trifolium pratense)

Does it work?

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 inhibit 24,25 the proliferation of breast cancer cells. Preliminary results suggest that it may also inhibit endometrial24 and prostate26 cancer cells. 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.

Citation

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

Document history

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.

References

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  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.
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  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.
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  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.
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  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.
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  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.
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  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.
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  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.
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