INDEX

Red Clover (Trifolium pratense)

Indications

Nutritive and fertility tonic, menopausal symptoms, premenstrual syndrome.

Mechanism of Action

Legume isoflavones are structurally similar to 17β-estradiol and are natural ligands of α and β estrogen nuclear receptors.1 Genistein, daidzein, and formononetin are three isoflavones that occur in Trifolium, and they are the most studied of all isoflavones. Several hundred studies have been published over the past decade on each individual molecule. Isoflavone phytoestrogens have been shown to act as either agonists or antagonists at estrogen receptors, depending on the tissue type, and, because of competitive binding, depending on the underlying hormonal status in the tissues.2 Trifolium may help maintain the health of breasts, heart, and bones.

Evidence-Based Research

Selective estrogen receptor modulators (SERMs) are commonly prescribed menopausal medications; however, they fail to alleviate hot flashes, fatigue, leg cramps, or nausea, and they may increase the risk of thrombosis.3,4 Natural medicines are highly sought after to more effectively treat common menopausal symptoms as well as avoid the risks associated with synthetic, semisynthetic, and other pharmaceutical options. Trifolium and other plants containing isoflavones are among the most used herbal and alternative medicines for treating menopausal symptoms. Although pharmaceutical hormone therapy is associated with an increased risk of breast cancer, Trifolium has shown no such risk. In fact, it protects the breast from overstimulation of endogenous hormones.2

Although some clinical studies have shown little to no relief of hot flashes from Trifolium,5,6 other trials have shown efficacy.7 One review of pooled human clinical trials reported Trifolium isoflavones at a dose of 80 mg/day to alleviate hot flashes, pain, and significantly improve mood and cognitive symptoms.8 A randomized controlled trial (RCT) of 150 healthy postmenopausal women investigated the effects of 60.8 mg of Trifolium isoflavones with 19.2 mg of soy isoflavones versus placebo on hot flushes. The isoflavones were associated with a significant reduction in hot flashes compared with placebo in one month’s time.9 Another RCT dosed 80 mg of Trifolium isoflavones or placebo to postmenopausal women for 90 days. After a washout period of 7 days the interventions were crossed over for another 90 days. Hot flashes were significantly reduced while using Trifolium and increased when on placebo.10 Another RCT investigated the effects of 40 mg of Trifolium compared with placebo, and no significant improvements were seen on hot flashes at this lower dose after 1 year’s time.11

Safety in Pregnancy and Breastfeeding

Although there have been no studies specifically investigating Trifolium in pregnancy or lactation, Trifolium in moderate doses is generally considered safe by most herbalists because of its historical use in fertility and miscarriage prevention teas. The plant is free of alkaloids or known toxins and highly nutritive.

General Safety

One clinical trial dosing 80 mg of Trifolium isoflavones reported that no side effects were encountered.10 A meta-analysis summarizing 17 published clinical trials on Trifolium showed no evidence of adverse events during short-term use.12

Unlike pharmaceutical hormone replacement therapy, Trifolium is reportedly helpful in treating menopausal symptoms and maintaining bone and cardiovascular health, with benign, if not beneficial, effects on the breast and endometrium.13 Also, unlike pharmaceutical hormones or SERMs, Trifolium isoflavones are not noted to have negative effects on serum lipids or to increase the risk or thrombi.9 The use of Trifolium to treat menopausal symptoms or surgical menopause seems to be safe for women who currently have or have a history of breast cancer.14 Conventional hormone replacement therapies increase mammographic breast density in postmenopausal women, whereas Trifolium isoflavones do not.6,15 Some studies on isolated Trifolium isoflavones have reported activity against breast cancer.16,17

Trifolium flavonoids may down-regulate cytochrome p450 enzymes and thereby interact with pharmaceuticals that are processed via the same pathway.18

Dosage

A dose of 80 mg of isoflavones has been used in various menopausal studies. Several hundred milligrams of the whole plant may be dosed once or twice a day.

Traditional Uses

Trifolium is a medicinal herb traditionally used as a nutritive and fertility tonic. Trifolium is in the bean family, and along with soy and other legume family plants, it is credited with hormonal benefits because of its phytoestrogen content. Phytoestrogens are plant-based molecules with hormone modulating effects. Much of Trifolium’s folkloric reputation for bone strengthening, fertility enhancement, miscarriage prevention, and menopause support are likely a result of its isoflavone phytoestrogen content. Several human and animal studies have attributed hypolipidemic, hypoglycemic, or antiatherosclerotic effects to Trifolium extract or isoflavones, all of which can be beneficial postmenopausally when a woman’s cardiovascular risk profile worsens.

References

1

Gen Physiol Biophys. 2013;32(4):467–78. Nuclear receptors – target molecules for isoflavones in cancer chemoprevention. Bialešová L, Brtko J, Lenko V, Macejová D.

2 Gynecol Endocrinol. 2012;28(1):29–33. Effects of Trifolium extracts on breast cancer cell migration and invasion. Mannella P, Tosi V, Russo E, Zullino S, Pancetti F, Gompal S, Polak K, Genazzani AR, Genazzani AD, Simoncini T.

3 Obstet Gynecol Surv. 2013;68(6):467–81. Update on raloxifene: mechanism of action, clinical efficacy, adverse effects, and contraindications. Gizzo S, Saccardi C, Patrelli TS, Berretta R, Capobianco G, Di Gangi S, Vacilotto A, Bertocco A, Noventa M, Ancona E, D’Antona D, Nardelli GB.

4 Ann Endocrinol (Paris). 2014;75(3):148–55. Hormonal prevention of breast cancer. Thomin A, Friszer S, Fajac A, Daraï É, Chabbert-Buffet N.

5 Am J Med. 2005;118 Suppl 12B:98–108. Menopause: a review of botanical dietary supplements. Low Dog T.

6 Breast Cancer Res. 2004;6(3):R170–9. Red-clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial [ISRCTN42940165]. Atkinson C, Warren RM, Sala E, Dowsett M, Dunning AM, Healey CS, Runswick S, Day NE, Bingham SA.

7 Maturitas. 2014;79(1):58–64. Trifolium extract for alleviating hot flushes in postmenopausal women: a meta-analysis. Gartoulla P, Han MM.

8 Maturitas. 2014;78(4):263–76. Effects of isoflavones and amino acid therapies for hot flashes and co-occurring symptoms during the menopausal transition and early postmenopause: a systematic review. Thomas AJ, Ismail R, Taylor-Swanson L, Cray L, Schnall JG, Mitchell ES, Woods NF.

9 Clin Exp Obstet Gynecol. 2013;40(3):337–41. Nonhormonal management of postmenopausal women: effects of a Trifolium based isoflavones supplementation on climacteric syndrome and cardiovascular risk serum profile. Mainini G, Torella M, Di Donna MC, Esposito E, Ercolano S, Correa R, Cucinella G, Stradella L, Luisi A, Basso A, Cerreto FV, Cicatiello R, Matteo M, De Franciscis P.

10 Gynecol Endocrinol. 2012;28(3):203–7. The effect of Trifolium isoflavone supplementation over vasomotor and menopausal symptoms in postmenopausal women. Lipovac M, Chedraui P, Gruenhut C, Gocan A, Kurz C, Neuber B, Imhof M.

11 Rev Assoc Med Bras. 2010;56(5):558–62. Effects of Trifolium pratense on the climacteric and sexual symptoms in postmenopause women. del Giorno C, Fonseca AM, Bagnoli VR, Assis JS, Soares JM Jr, Baracat EC.

12 Phytomedicine. 2007;14(2–3):153–9. Trifolium pratense isoflavones in the treatment of menopausal hot flushes: a systematic review and meta-analysis. Coon JT, Pittler MH, Ernst E.

13 Menopause. 2006;13(2):251–64. Clinical studies of Trifolium (Trifolium pratense) dietary supplements in menopause: a literature review. Booth NL, Piersen CE, Banuvar S, Geller SE, Shulman LP, Farnsworth NR.

14 J Br Menopause Soc. 2004;10 Suppl 1:7–12. Trifolium isoflavones in practice: a clinician’s view. Pitkin J.

15 Hum Reprod Update. 2010;16(6):745–60. Effects of isoflavones on breast density in pre- and post-menopausal women: a systematic review and meta-analysis of randomized controlled trials. Hooper L, Madhavan G, Tice JA, Leinster SJ, Cassidy A.

16 Horm Metab Res. 2012;44(13):943–8. Formononetin-induced apoptosis by activation of Ras/p38 mitogen-activated protein kinase in estrogen receptor-positive human breast cancer cells. Chen J, Sun L.

17 Gynecol Endocrinol. 2011;27(12):1037–42. Trifolium and soy isoflavones–an in vitro safety assessment. Reiter E, Gerster P, Jungbauer A.

18 Indian J Pharm Sci. 2014;76(3):261–6. Effect of Trifolium on CYP expression: An investigation of herb-drug interaction at molecular level. Tripathi A, Singh SP, Raju KS, Wahajuddin, Gayen JR.