Red Clover (Trifolium pratense)
  
Red Clover (Trifolium pratense)
Background
Red clover is a legume, which like soy contains "phytoestrogens" (plant-based chemicals that are similar to estrogen, and may act in the body like estrogen or may actually block the effects of estrogen). Red clover was traditionally used to treat asthma, pertussis, cancer, and gout. In modern times, isoflavone extracts of red clover are most often used to treat menopausal symptoms, as an alternative hormone replacement therapy, for high cholesterol, or to prevent osteoporosis. However, at this time, there are no high-quality human studies supporting the use of red clover for any medical condition.
Synonyms
Ackerklee (German), beebread, cow clover, genistein, isoflavone, isoflavone clover extract (ICE), meadow clover, phytoestrogen, Promensil®, purple clover, Rotklee (German), Rimostil®, trefoil, trefle des pres (French), trifolium pratense, Trinovin®, wild clover.
Evidence
These uses have been tested in humans or animals. Safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.
Uses based on scientific evidenceGrade*Menopausal symptoms
Laboratory research suggests that components of red clover called isoflavones have estrogen-like activity. Red clover isoflavones are proposed to reduce symptoms of menopause (such as hot flashes), and are popular for this use. However, most of the available human studies are poorly designed and short in duration (less than 12 weeks of treatment). In a well conducted, multicenter randomized, controlled clinical trial the safety and efficacy of two brands of red clover were studied as well as the effects of both brands compared to placebo on hot flashes. The two brands of red clover were Promensil® (82 mg of red clover), and Rimostil® (57 mg of red clover). The study included 252 postmenopausal women aged 45 to 60 years who were experiencing at least 35 hot flashes a week, and excluded vegetarians, those who consumed soy products more than once a week or took medications that would affect the absorption of the red clover. The study found that neither supplement had a significant effect on hot flashes or other symptoms of menopause. Another randomized, controlled clinical trial studied the effects of red clover (Promensil®) versus placebo on hot flashes. This was a smaller study and included only 30 postmenopausal women who were experiencing more than 5 hot flashes a week. This study found that red clover supplementation (Promensil®, providing 80 mg of red clover) significantly decreased the amount of hot flashes that the women experienced. As results of published studies conflict with each other, more research is needed before a clear conclusion can be drawn.
C
Hormone replacement therapy (HRT)
Laboratory research suggests that red clover isoflavones have estrogen-like activity. However, there is no clear evidence that isoflavones share the possible benefits of estrogens (such as effects on bone density). In addition, hormone replacement therapy itself is a controversial topic, with recent research reporting that the potential harm may outweigh any benefits.
C
High cholesterol
Red clover has not been clearly shown to have beneficial effects on blood cholesterol levels. One small randomized, controlled clinical trial studied the effects of red clover (86 mg/day) on blood lipids and insulin in pre-menopausal women. The study followed 12 pre-menopausal women for 3 cycles and found that there was no change in the women's lipid profile or their blood sugar or insulin levels. Due to conflicting study results, further research is needed in this area before a recommendation can be made.
C
Osteoporosis
It is not clear if red clover isoflavones have beneficial effects on bone density. Most studies of isoflavones in this area have looked at soy, which contains different amounts of isoflavones, as well as other non-isoflavone ingredients. More research is needed before a recommendation can be made.
C
Prostate enlargement (benign prostatic hypertrophy)
There is only limited study of red clover for benign prostatic hypertrophy. More research is needed before a firm conclusion can be drawn.
C
Prostate cancer
Red clover isoflavones may have estrogen-like properties in the body, and have been proposed as a possible therapy in prostate cancer and related hot flashes. Some isoflavones have also been shown in laboratory studies to have anti-cancer properties. Because there is no-well designed human research in this area, a recommendation cannot be made.
C
Cardiovascular - blood flow
Red clover has been shown to improve the flow of blood through arteries and veins. However there is limited study in this area and more research is needed before a conclusion can be drawn.
C
Diabetes
Red clover has been studied in patients with type 2 diabetes to determine potential benefits in diabetic complications such as high blood pressure and narrowing of the arteries and veins. A small randomized, controlled trial studied postmenopausal women with type 2 diabetes. Women were given red clover (approximately 50 mg/day) for 4 weeks and the effects were compared to placebo. Improvements were seen in blood pressure and in the function of the veins and arteries. Another small randomized, controlled clinical trial studied the effects of red clover (86 mg/day) on blood lipids and insulin in pre-menopausal women. The study followed 12 pre-menopausal women for 3 cycles and found that there was no change in the women's lipid profile or their blood sugar or insulin levels. Further research is needed before a recommendation can be made. If you have diabetes you should contact your health care provider before taking red clover.
C
* Key to grades
A: Strong scientific evidence for this use;
B: Good scientific evidence for this use;
C: Unclear scientific evidence for this use;
D: Fair scientific evidence against this use (it may not work);
F: Strong scientific evidence against this use (it likely does not work).
Uses based on tradition or theory
The below uses are based on tradition or scientific theories. They often have not been thoroughly tested in humans, and safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.
Acne, AIDS, antibacterial, antioxidant, anti-spasm, appetite suppressant, arthritis, asthma, "blood purification," bronchitis, burns, cancer prevention, canker sores, cough, chronic skin diseases, diuretic (increase urine flow), eczema, gout, hot flashes, indigestion, mastalgia (breast pain), premenstrual syndrome, psoriasis, sexually transmitted diseases, skin ulcers/sores, sore eyes, tuberculosis, whooping cough (pertussis).
Dosing
The below doses are based on scientific research, publications, traditional use, or expert opinion. Many herbs and supplements have not been thoroughly tested, and safety and effectiveness may not be proven. Brands may be made differently, with variable ingredients, even within the same brand. The below doses may not apply to all products. You should read product labels, and discuss doses with a qualified healthcare provider before starting therapy.
Standardization
Standardization involves measuring the amount of certain chemicals in products to try to make different preparations similar to each other. It is not always known if the chemicals being measured are the "active" ingredients. The brand of red clover extract used in most trials, and which is most commonly available, is Promensil®. Each tablet, composed of 40 milligrams total isoflavones, is standardized to contain the following components: 4 milligrams genistein; 3.5 milligrams daidzein; 24.5 milligrams biochanin A; and 8.0 milligrams formononetin.
Adults (18 years and older)
Menopausal symptoms : 40 milligrams, 80 milligrams, or 160 milligrams of red clover isoflavones per day (Promensil®) has been studied. Rimostil® (57 mg of red clover) has also been used.
Hormone replacement : 40 to 80 milligrams of red clover isoflavones per day (Promensil®) has been studied.
High cholesterol : 28 to 86 milligrams of red clover isoflavones per day (Rimostil®), or 80 milligrams of red clover isoflavones per day (Promensil®) has been studied.
Osteoporosis : 40 milligrams of red clover isoflavones per day (Promensil®) has been studied.
Benign prostatic hypertrophy : 40 milligrams of red clover isoflavones per day (Trinovin®) has been studied.
Diabetes : 50 milligrams and 86 milligrams per day of red clover isoflavones per day have been studied for diabetic complications.
Children (younger than 18 years)
There is not enough scientific evidence to recommend use of red clover in children.
Safety
The U.S. Food and Drug Administration does not strictly regulate herbs and supplements. There is no guarantee of strength, purity or safety of products, and effects may vary. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy. Consult a healthcare provider immediately if you experience side effects.
Allergies
People with known allergies or reactions to products containing red clover or isoflavones should avoid taking red clover.
Side Effects and Warnings
A small number of human studies using red clover extracts have all reported good tolerance, without serious side effects after up to one year of treatment. In theory, based on the estrogen-like action of red clover seen in laboratory studies, side effects may include weight gain or breast tenderness, although these have not been reported clearly in humans. In theory, menstrual changes and increased uterus cell growth (endometrial hyperplasia) may also occur, although preliminary short-term studies (less than 6 months) have found no increases in uterus wall (endometrial) thickness with red clover. Red clover may affect hormonal levels of gonadotropin releasing hormone (GrH), follicle stimulating hormone (FSH), and leutinizing hormone (LH), although early research has not found significant change in FSH or LH levels.
In theory, red clover may increase the risk of bleeding. However, there are no reliable human reports of bleeding with red clover. Caution is advised in patients with bleeding disorders or taking drugs that may increase the risk of bleeding. Dosing adjustments may be necessary.
Red clover has been studied for lowering blood sugar with inconclusive results. Caution is warranted until further research is available.
Pregnancy and Breastfeeding
Red Clover is not recommended during pregnancy and breastfeeding due to its estrogen-like activity. Red clover has been reported as a possible cause of infertility and abortion in grazing livestock.
References
1. Abernathy K, Brockie J, Suffling K, et al. An open study of the effects of a 40 mg isoflavone food supplement (derived from red clover), on menopausal symptoms [abstract]. Brit Menopause Soc (2001).
2. Atkinson C, Compston JE, Robins SP, et al. The effects of isoflavone phytoestrogens on bone: Preliminary results from a large randomized controlled trial. Endocr Soc Annu Meet Program 2000;82:196.
3. Baber RJ, Templeman C, Morton T, et al. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric 1999;2:85-92.
4. Barnes S. Phyto-oestrogens and osteoporosis: what is a safe dose? Br J Nutr. 2003 Jun;89 Suppl 1:S101-8.
5. 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 Feb;84 (2-3) :259-68.
6. 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 Apr;89(4):467-74.
7. Boue SM, Wiese TE, Nehls S, Burow ME, Elliott S, Carter-Wientjes CH, Shih BY, McLachlan JA, Cleveland TE. Evaluation of the estrogenic effects of legume extracts containing phytoestrogens. J Agric Food Chem. 2003 Apr 9;51(8):2193-9.
8. Clifton-Bligh PB, Baber RJ, Fulcher GR, et al. The effect of isoflavones extracted from red clover (Rimostil) on lipid and bone metabolism. Menopause 2001;8(4):259-265.
9. Garcia-Martinez MC, Hermenegildo C, Tarin JJ, Cano A. Phytoestrogens increase the capacity of serum to stimulate prostacyclin release in human endothelial cells. Acta Obstet Gynecol Scand. 2003 Aug;82(8):705-10.
10. Gerber G, Lowe FC, Spigekman S. The use of a standardized extract of red clover isoflavones for the alleviation of BPH symptoms. The Endocrine Society's 82nd Annual Meeting 2000;82:2359.
11. 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 2000;152(1):143-147.
12. 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. 2003 Sep;5(5):325-32.
13. 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.
14. Jarred RA, McPherson SJ, Jones ME, Simpson ER, Risbridger GP. Anti-androgenic action by red clover-derived dietary isoflavones reduces non-malignant prostate enlargement in aromatase knockout (ArKo) mice. Prostate. 2003 Jun 15;56(1):54-64.
15. Jarred RA, Keikha M, Dowling C, McPherson SJ, Clare AM, Husband AJ, Pedersen JS, Frydenberg M, Risbridger GP. Induction of apoptosis in low to moderate-grade human prostate carcinoma by red clover-derived dietary isoflavones. Cancer Epidemiol Biomarkers Prev. 2002 Dec;11(12):1689-96.
16. Knight DC. The effect of Promensil, an isoflavone extract, on menopausal symptoms. Climacteric 1999;2:79-84.
17. Moyad MA. Complementary/alternative therapies for reducing hot flashes in prostate cancer patients: reevaluating the existing indirect data from studies of breast cancer and postmenopausal women. Urology. 2002 Apr;59(4 Suppl 1):20-33.
18. Nachtigall LB, La Grega L, Lee WW, et al. The effects of isoflavones derived from red clover on vasomotor symptoms and endometrial thickness. 9th International Menopause Society World Congress on the Menopause 1999;331-336.
19. 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.
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. 2003 Jun 1;23(6):1066-71. Epub 2003 Apr 24.
21. 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 Jul 9;290(2):207-14.
22. Umland EM, Cauffield JS, Kirk JK, et al. Phytoestrogens as therapeutic alternatives to traditional hormone replacement in postmenopausal women. Pharmacother 2000;20(8):981-990.
23. van de Weijer PH, Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas. 2002 Jul 25;42(3):187-93.
24. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321-333.
January 01, 2004 
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