Red Clover

Overview
Red clover is a leguminous plant that is high in the plant phytoestrogens, the isoflavones, and has gained popularity as a treatment for menopausal symptoms for this reason. These isoflavones are popular for balancing the hormones in women’s health—especially menopause—because they are thought to act like very weak estrogens. The isoflavones are able to interact with the estrogen receptors on cell surfaces, and in doing so they are thought to both inact a very weak effect of estrogen, and maybe more importantly to compete with the more dangerous forms (higher levels of which cause the adverse effects of estrogen) of estrogen in the body.

The difference between the soy isoflavones and those from red clover is that soy contains only two types of isoflavones, genistein and daidzein, whereas, red clover has four types, genistein, daidzein, biochanin, and formononetin. There are many more studies on the soy isoflavones, but increasing studies on red clover that shows it may deliver the same if not better benefits.

Comments
Red clover seems like another good source of isoflavones, which is just starting to get clinical results. However, as it shares half of the same isoflavones with soy, the benefits should be similar for taking red clover.

Scientific Support
Menopausal Symptoms
Tice et al. (2003) conducted a randomized, double-blind, placebo-controlled study of the effect of two red clover products on menopausal women. The 252 participants were given either Promensil (82 mg total isoflavones daily), Rimostil (57 mg total isoflavones daily) or matched placebo for 12 weeks. The primary outcome measure was the number of hot flashes, while the secondary was adverse events and changes in quality of life. There were no significant differences found between the groups for any of the parameters measured. There was evidence, however, that Promensil reduced the hot flash frequency faster than either Rimostil or placebo.

Red clover extract was clinically tested for its effect on hot flash frequency in postmenopausal women in a randomized, double-blind, placebo-controlled study. The 30 participants were divided into two groups and given either 80 mg isoflavones (from red clover, Pomensil) or placebo daily for 12 weeks. The treatment group resulted in a significant reduction (44%) in hot flashes at the end of the 12 weeks of Promensil treatment (van de Weijer and Barentsen, 2002).

Cholesterol and Insulin Resistance
In order to determine if isoflavones (from red clover) had an effect on cholesterol homeostasis or insulin resistance in premenopausal women, Blakesmith et al., (2003) conduced a randomized, double-blind, placebo-controlled, parallel clinical study. The participants (25) were divided into two groups and given either a) one menstrual cycle of placebo and then three consecutive menstrual cycle of red clover isoflavone supplement (86 mg daily isoflavones) or b) four consecutive menstrual cycles of placebo. There were no significant effects found on cholesterol homeostasis or insulin resistance.

Howes et al. (2000) studied the effect of a red clover isoflavone extract in 66 postmenopausal women with plasma cholesterol levels between 5.0 and 9.0 mmol/l in a placebo-controlled, randomized, double-blind, ascending dose study. The isoflavone extract contained approximately 26 mg biochanin, 16 mg formoneonetin, 0.5 mg daidzein, and 1 mg genistein. The treatment period lasted for 4 weeks. There was no significant difference found between treatment with isoflavones and placebo in plasma lipids in women with moderately high cholesterol levels.

Nestel et al. (1999) studied whether isoflavone intake was able to reduce the elevated risk of cardiovascular disease associated with menopause in a double-blind, placebo-controlled study. Two 5-week periods of active treatment consisted of the administration of 40 mg and then 80 mg isoflavones derived from red clover. The effect on the cardiovascular risk was measured by measuring arterial compliance (the elasticity of the large arteries). Treatment with isoflavones from red clover was found to significantly improve the arterial compliance, and thus potentially reduce the risk of cardiovascular disease after menopause.

Isoflavone Absorption
In a clinical evaluation of the absorption of isoflavones from red clover vs. soy, 14 subjects were studied in a single-blind, randomized, placebo-controlled, crossover clinical trial. The soybean isoflavones and the red clover isoflavones were included in a breakfast cereal and administered as a meal for 2 weeks each. There was no significant difference between the two types of isoflavone sources in the urinary excretion, signifying no difference in absorption (Tsunoda et al., 2002).

Prostate Cancer
Jarred et al (2002) conducted a nonrandomized, nonblind, study to assess if there isoflavone consumption could be linked to prostate cancer incidence. Before surgery, 38 men who had been diagnosed with prostate cancer were given 160 mg daily of red clover derived isoflavones. The tissue upon radical prostatectomy was compared to historical specimens as a control. There were no differences found for serum PSA, Gleason score, serum testosterone, or biochemical factors. There was, however, a significant increase in apoptosis in prostate tumor cells of treated patients, especially in regions of low to moderate-grade cancer. The authors concluded that isoflavones may halt the progression of prostate cancer in low to moderate grade tumors, and that this may be a contributing factor in the lower incidence of prostate cancer in Asian men.

Safety / Dosage
The typical recommended dosage of isoflavones from red clover is 40-80 mg daily. There are no serious side effects associated with red clover extract.

References
1.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.
2.Howes JB, Sullivan D, Lai N, Nestel P, Pomeroy S, West L, Eden JA, Howes LG. 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 Sep;152(1):143-7.
3.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.
4.Nestel PJ, Pomeroy S, Kay S, Komesaroff P, Behrsing J, Cameron JD, West L. Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women. J Clin Endocrinol Metab. 1999 Mar;84(3):895-8.
5.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.
6.Tsunoda N, Pomeroy S, Nestel P. Absorption in humans of isoflavones from soy and red clover is similar.J Nutr. 2002 Aug;132(8):2199-201.
7.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.

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS