Red Clover

March 2005

Trifolium pratense L. Family: Fabaceae

Cow clover , meadow clover , purple clover , trefoil

Uses

Red clover flowers have been used traditionally as a sedative, to purify the blood, and to treat respiratory conditions; topical preparations have been used for psoriasis, eczema, and rashes, and to accelerate wound healing. More recently, clinical trials have been conducted examining red clover's use in the treatment of menopausal symptoms, but with minimal to no possible effects. A few additional studies have shown positive effects on cardiovascular health and bone density, although they have included only a small number of subjects.

Dosing

The traditional dose of red clover blossoms for sedation is 4 g. Red clover is now used primarily as a source of isoflavones. The usual dose is 40 to 80 mg/day of standardized isoflavones, typically containing biochanin A, formononetin, genistein, and daidzein. Several commercial preparations are available.

Contraindications

Contraindicated in patients with a history of breast cancer and during pregnancy or lactation.

Pregnancy/Lactation

Red clover has estrogenic activity. Avoid use.

Interactions

Isoflavonoids may interfere with hormonal agents; avoid use with oral contraceptives, estrogen, or progesterone therapies.

Adverse Reactions

Few adverse reactions have been reported in doses used in clinical trials. High doses of isoflavones have been associated with loss of appetite, pedal edema, and abdominal tenderness.

Toxicology

This perennial herb is commonly found growing in light sandy soil in meadows throughout Europe and Asia. It is naturalized in North America where its nitrogen-fixing properties are utilized for pasture renovation. The plant is low and bushy with several hairy stems arising from a taproot. Dense terminal heads of up to 125 fragrant red-to-purple flowers are borne at the end of the branched stems. The leaves occur in groups of 3 ovate leaflets; a characteristic lighter water mark in the shape of an inverted V is visible at the center of the group. ¹

Dried red clover flowers are used in traditional medicine to treat a wide spectrum of ailments. These include jaundice, cancer, mastitis, joint disorders, and respiratory conditions such as whooping cough and bronchial asthma. The plant is thought to purify the blood by promoting urine and mucus production, improving circulation, and stimulating secretion of bile. ² Red clover ointments have been used topically to accelerate wound healing and to treat psoriasis, eczema, and rashes. Respiratory complaints are treated with an infusion; fomentations and poultices have been used as topical applications for cancerous growths.

The main chemical classes contained in red clover are carbohydrates, isoflavones, flavonins, and saponins. Other constituents include coumaric acid, fats, minerals, and vitamins. A volatile oil that includes methyl salicylate is distilled from the flowers. ³ Isoflavones are often termed phytoestrogens because of their functional similarity to estrogens. The major isoflavones in red clover are biochanin A, formononetin, daidzein, and genistein; total phytoestrogen content is approximately 0.17%.

Much of the interest in red clover originated from observations of positive health benefits derived from the use of soy products. Both soy and red clover are sources of isoflavones and have similar estrogenic activity; in vitro studies have shown this to be approximately 1/400th that of 17-β-estradiol. ⁴

Menopause The use of red clover as a natural hormone replacement therapy has been postulated because of its estrogenic activity. Phytoestrogens appear to act as partial agonists in some tissues and antagonists in others, exhibiting hormonal and nonhormonal properties. ^5, They have a greater affinity for β- rather than α-estrogen receptors. Weak estrogenic activity has been demonstrated in rats. ^6, Several nonhormonal mechanisms have also been demonstrated, including tyrosine kinase inhibition, antioxidant activity, and effects on ion transport. ⁷

Results from clinical studies assessing the use of red clover isoflavones in menopause have been mixed. However, the North American Menopause Society recommends that red clover may be considered as an option for the treatment of menopausal symptoms as adverse effects appear to be minimal and some women appear to benefit from treatment. ⁵

Animal data Research reveals no animal data regarding the effects of red clover on menopause.

Clinical data Four studies investigating the effects of red clover extracts were included in a systematic review of herbal medicine products used to treat symptoms of menopause. ⁸ All trials used the proprietary product Promensil (Novogen Laboratories, North Sydney, Australia) containing biochanin A, formononetin, genistein, and daidzein. Use of the red clover supplement resulted in nonsignificant improvement over placebo in 2 trials; however, dietary isoflavone intake was not controlled, possibly affecting the validity of these results. In the remaining 2 trials, dietary intake of isoflavones was controlled and the patient population was comprised of women with a higher baseline frequency of vasomotor symptoms than in the negative studies; significant reduction in the incidence of hot flashes was associated with isoflavone supplementation in these trials. It was concluded that, although evidence for the use of red clover was not convincing, women with more severe menopausal symptoms might experience benefit. A large trial (N = 252), not included in the review, compared 2 commercial supplements ( Promensil and Rimostil ) with placebo over a 12-week period. ⁷ Similar reductions in mean daily hot flashes were observed in all 3 groups at 12 weeks although reduction of hot flashes was more rapid with Promensil than with placebo.

Cardiovascular effects Beneficial effects of soy protein on blood lipid profiles have been demonstrated. However, results from studies of red clover have been mixed, with either no effects on plasma lipids ^9, , ^10, or, with only modest improvements observed. ^11, , ¹² Results from studies investigating vascular effects of red clover have been more encouraging.

Animal data Research reveals no animal data regarding the use of red clover for cardiovascular effects.

Clinical data No improvements in cardiovascular risk factors were associated with the 1-year use of a red clover-derived isoflavone supplement by women aged 49 to 65 years. However, a trend toward potentially beneficial changes in triglycerides was observed in perimenopausal women. ¹¹ A small but significant decrease in triglyceride levels was observed in another study of women receiving Promensil or Rimostil . Women with elevated baseline triglyceride levels showed greatest improvement. ¹² However, the effect was probably too small to be clinically important. These studies suggest that isoflavones may not be responsible for the well-documented effects of soy protein on blood lipids.

Arterial compliance, an index of the elasticity of large arteries, improved in a small, short-term study of postmenopausal women receiving Promensil . ^10, These results were confirmed by a larger study of normotensive men and postmenopausal women. ¹³ Ambulatory blood pressure remained unchanged but total peripheral resistance improved in these patients. Subjects received 80 mg/day of a red clover-derived isoflavone supplement containing mostly biochanin A or formononetin; improvements were greatest in the formononetin group.

Effects on bone density Diets rich in soy protein have been associated with reduced incidence of hip fracture and attenuation of bone loss. Because of this, red clover has been investigated also.

Animal data Research reveals no animal data regarding the effects of red clover on bone density.

Clinical data Isoflavone supplementation was associated with reduced losses of bone mineral content and bone mineral density at the lumbar spine in a large study (N = 205). ¹⁴ Markers of bone formation were also increased in women, 49 to 65 years of age, who received Promensil for 12 months. Postmenopausal women appeared to gain most advantage. Between-group differences in bone mineral density at the hip were not significant. Another trial showed no differences in markers of bone turnover among menopausal women receiving Rimostil , Promensil , or placebo. ¹² However, the validity of the results may have been affected by the short study duration (12 weeks).

Other uses Biochanin A has been reported to inhibit carcinogenic activity in cell cultures. ^3, Men with low- to moderate-grade prostate carcinoma who received isoflavonoid supplements prior to radical prostatectomy showed no changes in serum prostate-specific antigen, serum testosterone, or biochemical factors. ¹⁵ However, analysis of prostatectomy specimens showed an increase in apoptosis, particularly in regions of low- to moderate-grade cancer, when compared with historical controls.

Formerly used as a sedative at doses of 4 g blossoms, red clover is now used chiefly as a source of isoflavones. Extracts standardized for isoflavone content (eg, Promensil and Rimostil ; Novogen Laboratories , North Sydney, Australia) have been used frequently in clinical trials. These tablets contain biochanin A, formononetin, genistein, and daidzein; Promensil contains a higher proportion of biochanin A and genistein and lower proportions of formononetin and daidzein than Rimostil . ⁶ The usual dosage is 40 to 80 mg/day of total isoflavones (1 to 2 tablets).

The estrogenic effects of red clover are well documented and may have an effect on the fetus. Use is contraindicated.

An additive effect may occur if the phytoestrogens of red clover are taken with hormonal therapies; avoid concurrent use with oral contraceptives, estrogen, or progesterone therapies.

Red clover contains coumarin derivatives; however, there is little risk of anticoagulant abnormalities. ^16, , ¹⁷

Few adverse effects of red clover have been reported in clinical trials. ^15, , ^18, Loss of appetite, pedal edema, and abdominal tenderness have been reported after administration of a high (4 or 8 mg/kg) dose of isoflavones (genistein, daidzein, glycitenz). ¹⁹ Free and total genistein and daidzein disappeared rapidly from the plasma in this study and appear unlikely to accumulate in the body with regular use 2 to 3 times daily.

The phytoestrogens in red clover may be expected to act through estrogenic mechanisms with the associated risk of estrogen-like adverse effects, including increased incidence of endometrial, ovarian, and breast cancers. Red clover induced a proliferation of estrogen-sensitive breast cancer cells in an in vitro study. ²⁰ However, another study showed that mammographic breast density, a marker for estrogenic and antiestrogenic effects, was unaffected by administration of Promensil for 1 year in women 49 to 65 years of age. ^21, A small pilot study found no antiproliferative effects on the endometrium associated with use of red clover isoflavones. ²²

Infertility and growth disorders have been observed in grazing animals receiving high proportions of red clover in their feed. This has been attributed to the estrogenic activity of red clover. A syndrome characterized by infertility, abnormal lactation, dystonia, and prolapsed uterus, known as clover disease, has been described in sheep.

1. Purdue Forage Information. Red Clover, Trifolium pratense L. Available at: http://www.agry.purdue.edu/ext/forages/publications/legumes/red_clover.htm . Accessed February 11, 2005.

2. Alternative Medicine. Red Clover. Health and Age . 2004. Available at: http://www.healthandage.com/html/res/com/ConsHerbs/RedCloverch.html . Accessed February 11, 2005.

3. Newall CA, Anderson LA, Phillipson JD, eds. Herbal Medicines: A Guide for Health-Care Professionals . London: Pharmaceutical Press;1996.

4. Oerter Klein K, Janfaza M, Wong JA, Chang RJ. Estrogen bioactivity in fo-ti and other herbs used for their estrogen-like effects as determined by a recombinant cell bioassay. J Clin Endocrinol Metab . 2003;88:4077-4079. PubMed

5. North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause . 2004;11:11-33.

6. Burdette JE, Liu J, Lantvit D, et al. Trifolium pratense (red clover) exhibits estrogenic effects in vivo in ovariectomized Sprague-Dawley rats. J Nutr . 2002;132:27-30. PubMed

7. 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 . 2003;290:207-214. PubMed

8. Huntley AL, Ernst E. A systematic review of herbal medicinal products for the treatment of menopausal symptoms. Menopause . 2003;10:465-476. PubMed

9. Blakesmith SJ, Lyons-Wall PM, George C, Joannou GE, 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. PubMed

10. 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 . 1999;84:895-898. PubMed

11. Atkinson C, Oosthuizen W, Scollen S, Loktionov A, Day NE, Bingham SA. Modest protective effects of isolflavones from red clover-derived dietary supplement on cardiovascular disease risk factors in perimenopausal women, and evidence of an interaction with ApoE genotype in 49-65 year-old women. J Nutr . 2004;134:1759-1764. PubMed

12. 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 . 2004;48:209-218. PubMed

13. 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 . 2003;23:1066-1071. PubMed

14. 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. PubMed

15. 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 . 2002;11:1689-1696. PubMed

16. Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm . 2000;57:1221-1230. PubMed

17. Booth NL, Nikolic D, van Breeman RB, et al. Confusion regarding anticoagulant coumarins in dietary supplements. Clin Pharmacol Ther . 2004;76:511-516. PubMed

18. Howes JB, Bray K, Lorenz L, Smerdely P, Howes LG. The effects of dietary supplementation with isoflavones from red clover on cognitive function in postmenopausal women. Climacteric . 2004;7:70-77. PubMed

19. Busby MG, Jeffcoat AR, Bloedon LT, et al. Clinical characteristics and pharmacokinetics of purified soy isoflavones: single-dose administration to healthy men. Am J Clin Nutr . 2002;75:126-136. PubMed

20. Bodinet C, Freudenstein J. Influence of marketed herbal menopause preparations on MCF -7 cell proliferation. Menopause . 2004;11:281-289. PubMed

21. Atkinson C, Warren RM, Sala E, et al. Red-clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial [ISRCTN42940165]. Breast Cancer Res . 2004;6:RI70-179.

22. Beck V, Unterrieder E, Krenn L, Kubelka W, Jungbauer A. Comparison of hormonal activity (estrogen, androgen and progestin) of standardized plant extracts for large scale use in hormone replacement therapy. J Steroid Biochem Mol Biol . 2003;74:259-268. PubMed