Red Clover

• How It Works

  Red clover may help reduce menopausal symptoms, but additional study is needed.

  Red clover contains compounds similarly found in soy, known as isoflavones. These include biochanin, daidzein, formononetin and genistein. Although red clover isoflavones show hormonal activity in laboratory experiments, their effects in the human body are less clear.

  Studies on whether red clover may help reduce menopausal symptoms are mixed, and additional study is needed to confirm positive effects and safety with long-term use. One study in menopausal women suggests that red clover extract can improve elasticity of major arteries. The loss of elasticity can contribute to increased blood pressure, causing the heart to work harder. However, it is not known if red clover can protect against the development of heart disease, and this will also require more clinical trials.

  Red clover extract can stimulate the production of estrogen receptor-positive breast cancer cells in laboratory experiments, indicating that this herb may not be helpful for women with estrogen-sensitive cancers. In other experiments, red clover stopped growth of normal prostate cells and increased prostate cancer cell resistance to high-dose radiation. Therefore, patients with estrogen receptor-positive cancers or undergoing radiotherapy for prostate cancer should avoid using red clover.

• Purported Uses
  • To relieve chest congestion
    Evidence for this use is lacking.
  • To relieve the symptoms of menopause
    Studies on whether red clover may help reduce menopausal symptoms are mixed, and additional study is needed to confirm any positive effects as well as safety with long-term use.
  • To prevent heart disease in postmenopausal women
    A few clinical trials have looked at the effects of red clover on development of risk factors for heart disease in postmenopausal women, with no strong evidence that it helps. Most studies found that red clover had no effect on blood cholesterol or triglyceride levels. One clinical trial found that red clover increased the elasticity of major arteries, which may help prevent a gradual rise in blood pressure that can contribute to heart disease.
  • To stop muscle spasms
    Evidence for this use is lacking.
• Do Not Take If
  • You are taking warfarin or other blood thinners: Red clover can increase the risk of bleeding.
  • You have a hormone-sensitive disease such as estrogen receptor-positive breast cancer, ovarian cancer, endometriosis: Red clover may have estrogenic activity and should be avoided or used cautiously by patients with estrogen-sensitive disease.
  • You are taking methotrexate: Red clover may cause toxic effects, including severe vomiting and pain in the upper abdomen.
• Side Effects

  Case reports
  Bleeding around the brain or skull: Related to herbal supplements containing red clover used for menopausal symptoms. In one case, the issue resolved after supplement discontinuation. In another, the patient required intensive medical interventions to resolve issues.

• Brand Name

  Promensil®

• Scientific Name

  Trifolium pratense

• Clinical Summary

  Red clover is a perennial herb traditionally used to treat skin disorders such as psoriasis and eczema, whooping cough, and mastitis. It contains compounds known as isoflavones that act as phytoestrogens. An isoflavone extract is widely promoted as a dietary supplement to relieve menopausal symptoms.

  Red clover extract was shown to act as an estrogen agonist and stimulate proliferation of ER-positive breast cancer cells in vitro ⁽¹⁾. However, the isoflavone Biochinin A inhibited aromatase activity and expression ⁽²⁾, thereby conferring a protective effect. In other studies, isoflavone-enriched extracts demonstrated neuroprotective effects in human cortical neurons ^(3) (4) and reduced skin aging in mice by increasing the amount of collagen ⁽⁵⁾.

  Clinical data show that supplementation with red clover isoflavones improves menopausal symptoms compared with placebo ^(7) (8), but systematic reviews are mixed ^{(9) (24) (10)}. In postmenopausal women, supplementation alleviated vasomotor and menopausal symptoms ^(18) (25). Isoflavones may also improve bone loss ⁽¹¹⁾. In a trial involving osteopenic postmenopausal women, a red clover extract rich in isoflavones, aglycones, and probiotics attenuated bone mineral density loss caused by estrogen deficiency and improved bone turnover ⁽²⁶⁾. Dietary isoflavone intake also improved arterial compliance, an index of large artery elasticity which is an important cardiovascular risk factor ⁽¹²⁾.

  Of concern are findings that red clover inhibits the growth of normal prostate cells and increases resistance of prostate cancer cells to high-dose radiation in vitro ⁽¹⁵⁾. Patients should consult with their physicians before taking red clover supplements.

• Purported Uses
  • Chest congestion
  • Menopausal symptoms
  • Spasms
• Mechanism of Action

  Formononetin, an isoflavone, induced apoptosis in human breast cancer cells by activating the Ras-p38 mitogen-activated protein kinase in ER-positive breast cancer cells ⁽²³⁾. It also inhibited proliferation of human osteosarcoma U2SO cells by decreasing expression of miR-375 and Bcl-2, an apoptotic repressor, while increasing Bax, a pro-apoptotic protein  ⁽²⁷⁾. The isoflavone Biochanin A inhibited activity and gene expression of aromatase, an enzyme that catalyzes the conversion of androgen to estrogen ⁽²⁾. In addition, it protected dopaminergic neurons against lipopolysaccharide-induced damage by inhibiting microglial activation and proinflammatory factors ⁽³⁾. An isoflavone-enriched fraction showed neuroprotective activity in human cortical neurons as well, possibly due to antioxidant and estrogenic effects ⁽⁴⁾.

  In a murine model, red clover isoflavones reduced skin aging induced by estrogen deprivation following ovariectomy ⁽⁵⁾.

• Contraindications
  • Patients with hormone-sensitive cancers should avoid red clover because it has estrogenic activity ⁽²¹⁾.
  • Red clover may increase effects of anticoagulants and antiplatelet drugs ⁽²⁰⁾.
  • Red clover causes toxic effects when used with methotrexate ⁽¹⁹⁾.
• Adverse Reactions

  Case reports

  Subdural hematoma: In a 65-year-old woman with no other risk factors for bleeding except long-term use of red clover supplements for postmenopausal symptoms. After postoperative re-hemorrhage, an intraoperative thromboelastogram confirmed that antiplatelet effects were more likely than coumarin toxicity. There was no further bleeding after the patient was subsequently treated with tranexamic acid and platelet transfusions ⁽⁶⁾.

  Subarachnoid hemorrhage: In a 53-year-old woman following use of an herbal supplement containing red clover, dong quai, and Siberian ginseng for perimenopausal hot flashes. Symptoms resolved after supplement discontinuation  ⁽¹⁶⁾.

• Herb-Drug Interactions

  Anticoagulants / Antiplatelets: Red clover may increase their effects ⁽²⁰⁾.
  Cytochrome P450 enzymes: Red clover can inhibit CYP1A2/2C8/2C9/2C19/2D6 and 3A4, and may interact with substances metabolized by these enzymes ^(17) (28).
  Methotrexate: Red clover has been reported to cause toxicity, resulting in severe vomiting and epigastric pain, when used along with methotrexate injections ⁽¹⁹⁾.

• References

  1. Le Bail JC, Champavier Y, Chulia AJ, Habrioux G. Effects of phytoestrogens on aromatase, 3beta and 17beta-hydroxysteroid dehydrogenase activities and human breast cancer cells. Life Sci. 2000;66(14):1281-1291.

  2. Wang Y, Man Gho W, Chan FL, Chen S, Leung LK. The red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expression. Br J Nutr 2008;99(2):303-310.

  3. Chen HQ, Jin ZY, Li GH. Biochanin A protects dopaminergic neurons against lipopolysaccharide-induced damage through inhibition of microglia activation and proinflammatory factors generation. Neurosci Lett 2007;417(2):112-117.

  4. Occhiuto F, Zangla G, Samperi S, et al. The phytoestrogenic isoflavones from Trifolium pratense L. (Red clover) protects human cortical neurons from glutamate toxicity. Phytomedicine 2008.

  5. Circosta C, De Pasquale R, Palumbo DR, Samperi S, Occhiuto F. Effects of isoflavones from red clover (Trifolium pratense) on skin changes induced by ovariectomy in rats. Phytother Res 2006;20(12):1096-1099.

  6. Hall S, Walshe E, Ajayi C, et al. Acute-on-chronic subdural hematoma in a patient taking Red Clover herbal supplement: A case report. Surg Neurol Int. 2018;9:43.

  7. Hidalgo LA, Chedraui PA, Morocho N, Ross S, San Miguel G. The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: a randomized, double-blind, placebo-controlled study. Gynecol Endocrinol 2005;21(5):257-264.

  8. van de Weijer PH, Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas 2002;42(3):187-193.

  9. Coon JT, Pittler MH, Ernst E. Trifolium pratense isoflavones in the treatment of menopausal hot flushes: a systematic review and meta-analysis. Phytomedicine 2007;14(2-3):153-159.

  10. Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007(4):CD001395.

  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(2):326-333.

  12. 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(3):895-898.

  13. Brandli A, Simpson JS, Ventura S. Isoflavones isolated from red clover (Trifolium pratense) inhibit smooth muscle contraction of the isolated rat prostate gland. Phytomedicine. 2010 Sep;17(11):895-901.

  14. Tava A, Ramella D, Grecchi M, et al.Volatile constituents of Trifolium pratense and T. repens from N.E. Italian alpine pastures. Nat Prod Commun. 2009 Jun;4(6):835-8.

  15. Hasan Y, Schoenherr D, Martinez AA, et al. Prostate-specific natural health products (dietary supplements) radiosensitize normal prostate cells. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3):896-904.

  16. Friedman JA, Taylor SA, McDermott W, Alikhani P. Multifocal and recurrent subarachnoid hemorrhage due to an herbal supplement containing natural coumarins. Neurocrit Care. 2007;7(1):76-80.

  17. Unger M, Frank A. Simultaneous determination of the inhibitory potency of herbal extracts on the activity of six major cytochrome P450 enzymes using liquid chromatography/mass spectrometry and automated online extraction. Rapid Commun Mass Spectrom. 2004;18(19):2273-81.

  18. Lipovac M, Chedraui P, Gruenhut C, et al. The effect of red clover isoflavone supplementation over vasomotor and menopausal symptoms in postmenopausal women. Gynecol Endocrinol. 2012 Mar;28(3):203-7.

  19. Orr A, Parker R. Red clover causing symptoms suggestive of methotrexate toxicity in a patient on high-dose methotrexate. Menopause Int. 2013 Sep;19(3):133-4.

  20. Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm. 2000 Jul 1;57(13):1221-7.

  21. Booth NL, Overk CR, Yao P, et al. The chemical and biologic profile of a red clover (Trifolium pratense L.) phase II clinical extract. J Altern Complement Med. 2006 Mar;12(2):133-9.

  22. Howes J, Waring M, Huang L, Howes LG. Long-term pharmacokinetics of an extract of isoflavones from red clover (Trifolium pratense). J Altern Complement Med. 2002 Apr;8(2):135-42.

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

  24. Myers SP, Vigar V. Effects of a standardised extract of Trifolium pratense (Promensil) at a dosage of 80mg in the treatment of menopausal hot flushes: A systematic review and meta-analysis. Phytomedicine. 2017 Jan 15;24:141-147.

  25. Shakeri F, Taavoni S, Goushegir A, Haghani H. Effectiveness of red clover in alleviating menopausal symptoms: a 12-week randomized, controlled trial. Climacteric. 2015;18(4):568-73.

  26. Lambert MNT, Thybo CB, Lykkeboe S, et al. Combined bioavailable isoflavones and probiotics improve bone status and estrogen metabolism in postmenopausal osteopenic women: a randomized controlled trial. Am J Clin Nutr. 2017 Sep;106(3):909-920.

  27. Hu W, Xiao Z. Formononetin induces apoptosis of human osteosarcoma cell line U2OS by regulating the expression of Bcl-2, Bax and MiR-375 in vitro and in vivo. Cell Physiol Biochem. 2015;37(3):933-9.

  28. Arora S, Taneja I, Challagundla M, Raju KS, Singh SP, Wahajuddin M. In vivo prediction of CYP-mediated metabolic interaction potential of formononetin and biochanin A using in vitro human and rat CYP450 inhibition data. Toxicol Lett. 2015 Nov 19;239(1):1-8.