Trifolium pratense L. Family: Fabaceae

Overview

Red clover (RC) is a short-lived perennial herb growing 1 to 2 feet that produces purplish-pink tubular flowers.¹ Native to Europe, Asia, and Africa,² the herb is widely cultivated for its flowers and as a green manure and nitrogen-rich crop.¹ The genus name Trifolium is derived from the Latin tres meaning three and folium for leaf; the species pratense is Latin for growing in meadows.³

History and Cultural Significance

In Greek and Roman mythology, the three-leaf clover represents the triad goddesses.³ The rare four-leaf clover became a popular Christian symbol due to the cross shape. In medieval folk rhyme, the four-leaf clover symbolizes complete happiness. Each leaf is thought to represent a different aspect of happiness including fame, wealth, faithful lover, and excellent health.³

RC leaves are eaten as salad greens and the flowers are dried for use in teas. The Chinese have traditionally used an infusion of RC flowers internally as an expectorant, while Russians used an infusion to treat bronchial asthma.² European cultures also utilized RC as a medicinal herb to aid in liver and digestive ailments.² Various Native American cultures ate the leaves as food and used the plant for sore eyes and in a salve for burns,² as well as for whooping cough, fevers, menopause, and cancers.⁴

RC is an excellent forage crop for hay, silage, and livestock grazing, and it is also recognized for its importance in soil conservation and crop rotation due to its ability to fix nitrogen in soil.⁵

Recent Research

Recent research on RC has focused on its isoflavone content, as RC is a rich source of four dietary isoflavones—formononetin, daidzein, genistein, and biochanin A. High dietary intake of these phytoestrogens (mainly as found in soy foods) has been implicated in buffering the effect of reduced estrogen in menopausal women.

In a systematic review of herbs used to treat menopausal symptoms, 4 studies focused on RC. The review's authors concluded that RC may possibly be beneficial for certain menopausal symptoms.⁶ In 2 of the reviewed trials, an RC extract standardized to 40 mg of isoflavones reduced the frequency and severity of hot flashes by about 50% compared to placebo.^7,8 A subsequent trial showed no statistically significant benefits of 2 red clover preparations over placebo in reducing hot flashes.⁹ However, despite a growing body of clinical data suggesting benefits in the treatment of various menopause symptoms, a systematic review of 5 randomized trials on RC in menopausal women found no statistically significant effect of RC on hot flash frequency.¹⁰

Two other trials suggest that the isoflavones in RC may slow the rate of bone loss and may even help build bone in post-menopausal women. One study showed decreased bone loss over 12 months compared to placebo, concluding that RC isoflavones may have a protective effect on the lumbar spine in women.¹¹ Another trial demonstrated a significant increase in the cortical bone of the proximal radius and ulna after 6 months of use.¹²

RC isoflavones have numerous potential benefits for cardiovascular health. One clinical trial tested the effects of purified RC isoflavones on total cholesterol, concluding that these isoflavones provided no significant benefits on LDL (low-density lipoproteins, "cholesterol"), HDL (high-density lipoproteins, "good cholesterol"), or total cholesterol.¹³ Several other trials suggest that RC isoflavones have beneficial effects on lipid levels in men and women.^12,14,15,16 These include the following: a significant increase in HDL cholesterol in post-menopausal women,¹² a significant decrease in triglyceride levels among women taking 2 standardized RC extracts compared to placebo,¹⁴ and a lowered LDL cholesterol in men using biochanin A enriched isoflavone extract from RC.¹⁵ A previous trial showed an increase in arterial compliance (a marker for potential hypertension) but no reduction of cholesterol in menopausal women¹⁷ or menopausal women with mild to moderately high cholesterol¹⁸; a modest reduction was shown in another trial.¹⁴ Another potential cardiovascular benefit of RC isoflavones is their apparent ability to reduce arterial stiffness and vascular resistance, thereby lowering the risk of cardiovascular disease. One clinical study suggests that dietary supplementation with RC isoflavones significantly lowers blood pressure and may benefit endothelial function in postmenopausal type-2 diabetic women.¹⁹ Another showed that RC isoflavones reduced arterial stiffness and vascular resistance in normotensive men and postmenopausal women.²⁰

In clinical trials involving over 1,000 women, standardized RC extracts were well tolerated and resulted in no reported adverse events. The mildly estrogenic activity of RC isoflavones is many times less than that of steroidal estrogen. One study in pre-menopausal women demonstrated an anti-estrogenic effect by relieving breast pain associated with cyclical mastalgia.²¹ Another trial on the long-term effect of an RC-derived isoflavone supplement taken daily for 1 year concluded that (unlike conventional hormone replacement therapy) the RC supplement did not increase mammographic breast density.^22,23

RC extracts have also shown potential for men in prostate health. Epidemiological evidence (i.e., from population studies) suggests that a high dietary intake of isoflavones reduces the risk of prostate cancer and promotes general prostate health.²⁴ In a clinical trial, isoflavones induced apoptosis (programmed cell death) in moderate-grade tumors; this related data suggests that RC may help slow or stop growth of prostate cancer.²⁵ Another review of phytotherapies for men with benign prostatic hyperplasia (BPH) concludes that isoflavones, particularly RC extract, are potential therapies for promoting prostate health in men with the non-cancerous prostate growth associated with advancing age.²⁶

While there is growing clinical evidence for the benefits of RC extracts, most trials have been relatively small. Larger studies are needed for conclusive evidence on RC and/or RC-derived isoflavones for the potential benefits of lowering cholesterol and blood-pressure or the management of menopausal symptoms. Potential also exists for RC extracts as a source of dietary isoflavones for prostate and cardiovascular health in men.

References

1. Bown D. The Herb Society of America New Encyclopedia of Herbs & Their Uses. New York: DK Publishing, Inc; 2001.

2. Kelly G, Husband A, Waring M. Standardized red clover extract clinical monograph. Natural Products Research Consultants; 1998.

3. Onstad D. Whole Foods Companion. White River Junction, VA: Chelsea Green Publishing Co; 1996.

4. Moerman DE. Native American Ethnobotany. Portland, OR: Timber Press; 1998.

5. Smith R. Red Clover in the "Twenty-First" Century; 2000. Available at: http://www.uwex.edu/ces/forage/wfc/proceedings2000/smith.htm. Accessed December 26, 2005.

6. Huntley AL, Ernst E. A systematic review of herbal medicinal products for the treatment of menopausal symptoms. Menopause. September-October 2003;10(5):465-476.

7. Van de Weijer P, Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas. 2002;42:187-193.

8. Jeri, A. The use of isoflavone supplement to relieve hot flushes. The Female Patient. 2002;27:45-50.

9.Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Phytoestrogen supplements for the treatment of hot flashes: the isoflavone clover extract (ICE) study: a randomized controlled trial. JAMA. July 9, 2003;290(2):207-214.

Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol. October 2004;104(4):824-836.

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;326-333.

12. Clifton-Bligh P, Baber R, Fulcher G, Nery M, Moreton T. The effect of isoflavones extracted from red clover (Rimostil) on lipid and bone metabolism. Menopause. July-August 2001;8(4):259-265.

13. Blakesmith S, Lyons-Wall P, George C, Joannou G, Petocz P, Samman S. Effects of supplementation with purified red clover (Trifolium pratense) isoflavones on plasma lipids and insulin resistance in healthy premenopausal women. Br J Nutr. 2003;89:467-474.

14. Schult TM, Ensrud KE, Blackwell T, Ettinger B, Wallace R, Tice JA. Effect of isoflavones on lipids and bone turnover markers in menopausal women. Maturitas. July 15, 2004;48(3):209-218.

15.Nestel P, Cehun M, Chronopoulos A, DaSilva L, Teede H, McGrath B. A biochanin-enriched isoflavone from red clover lowers LDL cholesterol in men.Eur J Clin Nutr. March 2004;58(3):403-408.

16. Campbell M, Woodside JV, Honour JW, Morton MS, Leathem AJ. Effect of red clover-derived isoflavone supplementation on insulin-like growth factor, lipid and antioxidant status in healthy female volunteers: a pilot study. Eur J Clin Nutr. 2004:58;173-179.

17. 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. March 1999;84(3):895-898.

18. Howes JB, Sullivan D, Lai N, et al. The effects of dietary supplementation with isoflavones from red clover on the lipoprotein profiles of post menopausal women with mild to moderate hypercholesterolaemia. Atherosclerosis. September 2000;152(1):143-147.

19. Howes JB, Tran D, Brillante D, Howes LG. Effects of dietary supplementation with isoflavones from red clover on ambulatory blood pressure and endothelial function in postmenopausal type 2 diabetes. Diabetes Obes Metab. September 2003;5(5):325-332.

20. Teede HJ, McGrath BP, DeSilva L, Cehun M, Fassoulakis A, Nestel PJ. Isoflavones reduce arterial stiffness: a placebo-controlled study in men and postmenopausal women.Arterioscler Thromb Vasc Biol. June 1, 2003;23(6):1066-1071.

21. Ingram D, Hickling C, West L, Mahe L, Dunbar P. A double-blind randomized controlled trial of isoflavones in the treatment of cyclical mastalgia. Breast. April 2002;11(2);170-174.

22. Powles T. Isoflavones and Women's Health. Breast Cancer Res. 2004;6(3):140-142.

23. Atkinson C, Warren RM, Sala E, Dowsett M, Dunning AM, Healey CS, et al. Red clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial. Breast Cancer Res. 2004;6(3):170-179.

24. Griffiths K, Denis L, Turkes A, Morton MS. Phytoestrogens and diseases of the prostate gland. Bailliere's Clin Endrocrinol Metab. December 1998;12(4):625-647.

25. Jarred RA, Keikha M, Dowling C, et al. Induction of apoptosis in low to moderate- grade human prostate carcinoma by red clover-derived dietary isoflavones. Cancer Epidemiol Biomarkers Prev. December 2002;11(12):1689-1696.

26. Katz, A. Flavonoid and botanical approaches to prostate health. J Altern Complement Med. December 2002;8(6):813-821.