Articles

Red Clover

Plant Part Used

Flowering tops/heads

Active Constituents

Flavonoid glycosides (including the isoflavones formononetin, daidzein, genistein, biochanin A, and the flavonoid quercetin), coumarins, polysaccharides. (1) [span class=alert]

This section is a list of chemical entities identified in this dietary supplement to possess pharmacological activity. This list does not imply that other, yet unidentified, constituents do not influence the pharmacological activity of this dietary supplement nor does it imply that any one constituent possesses greater influence on the overall pharmacological effect of this dietary supplement.[/span]

Introduction

Red clover is a perennial herb, commonly found in Mediterranean and Red Seas countries. It has been used traditionally as a medicinal agent by Asian, European, and Native American cultures as an expectorant, in asthma, and as an alterative (blood purifier) to treat psoriasis, eczema, and other chronic skin conditions. (2)

There has been a great deal of research and reviews on the effects of phytoestrogens (plants that contain chemical entities that have estrogenic activities in the body) as they relate to menopausal symptoms. (3) , (4) Much of this research has been on the use of soy products and its constituents (genistein and daidzein), or the phytoestrogen containing black cohosh (formononetin). (5) , (6) , (7)

Recently, a proprietary extract of red clover, standardized to the phytoestrogen content, has gained a great deal of attention in the management of menopause and related symptoms. Research has focused on the red clover extract, which contains four principle phytoestrogens (biochanin A, fomonontein, genistein, and daidzein), all with reported levels of estrogen-like activity. (8) , (9)

Interactions and Depletions

Interactions

Dosage Info

Dosage Range

500mg (standardized extract) daily.

Fluid extract (1:1w/v): 10-30 drops, 3 times daily.

Most Common Dosage

500mg (standardized extract) daily.

Fluid extract (1:1w/v):15 drops, 3 times daily

Standardization

[span class=doc]Standardization represents the complete body of information and controls that serve to enhance the batch to batch consistency of a botanical product, including but not limited to the presence of a marker compound at a defined level or within a defined range.[/span]

The most current available medical and scientific literature indicates that this dietary supplement should be standardized to 40mg total isoflavones per dose, comprised of the isoflavones genistein (4mg), daidzein (3.5mg), biochanin A (24.5mg), and formononetin (8mg).

Uses

Frequently Reported Uses

  • Phytoestrogenic
  • Menopausal And Postmenopausal Complaints And Imbalances
  • PMS
Other Reported Uses
  • Alterative

Toxicities & Precautions

General

Red clover is reported safe in recommended dosages.

Health Conditions

Red clover contains coumarins. Although no adverse effects related to the coumarins have been reported, large doses may alter the course of therapy in patients with bleeding or clotting disorders. (10)

Pregnancy/ Breast Feeding

Do not use in pregnancy and lactation.

Age Limitations

Do not use in children under 2 years of age unless recommended by a physician.

Pharmacology

Red clover contains biochanin A and formononetin which are metabolized to genistein and daidzein, respectively. These isoflavones have been reported alone or in combination to have the following in vitro and in vivo effects:

Estrogenicity - Red clover isoflavones were shown to have oestrogenic effects.(57) They interact with human estrogen receptor sites (11) and their estrogenic effect relative to 17 beta-estradiol is between 1-5 x 10-3. (12)

Opiate activity – Red clover isoflavones were shown to bind with opiate receptors.(58)

Steroidogenesis - Isoflavones modulate a range of enzymes that regulate the production, metabolism, and function of steroidal hormones, including: inhibiting 17 beta-hydroxysteroid dehydrogenase which is involved in the synthesis of 17 beta-estradiol; (13) inhibiting aromatase which converts androstenedione to estrone; (14) and inhibiting 5-alpha-reductase which converts testosterone to dihydrotestosterone. (15) Other activities include inhibition of the oxidation of steroid hormones (16) and the promotion of the production of sex-hormone binding globulin (SHBG) by liver cells. (17)

Antioxidant - Isoflavones are antioxidants as well as promoting the activity of antioxidant enzymes in gut and skin. (18),(19),(59),(60),(61) They also inhibit the oxidation of LDL cholesterol (20),(21),(62) and lipid peroxidation in vivo. (63)

Calcium metabolism and bone turnover - Isoflavones promote calcium storage in cells, and inhibit osteoclast activityand differentiation by increasing apoptosis via caspase 3 pathway. (22) , (23) , (64) They may also maintain bone density, as reported in animal studies. (24),(65) Recent human studies reported that isoflavones from red clover selectively increased cortical bone density of the proximal radius and ulna. (25) , (26)

Cell growth and differentiation - Genistein is an inhibitor of a range of enzymes that modulate cell transduction processes involved in cell growth and differentiation; the principal enzymes are protein tyrosine kinases, and DNA topoisomerases. (27) , (28) , (29) Genistein blocks the growth of normal human lymphocytes and human leukemic cells by arresting growth in the G2/M phase of the cell cycle. (30) Genistein induces terminal differentiation and inhibits proliferation of human and rodent leukemic and melanoma cells and it also induces apoptosis of mouse leukemic cells in vivo. (31) , (32)

Anticancer activity (in vitro) - Isoflavones (mostly genistein) have been reported to be inhibitory in vitro to the following human cell lines: melanoma, (33) leukemia, (34) , (35) breast cancer, (36) , (37) gastrointestinal cancers, (38) , (39) prostate cancer, (40) and neuroblastoma (41) among others.

Anticancer activity (in vivo) - Rodents treated with genistein report increased resistance to chemically induced breast cancer. (42) However, it has not been fully elucidated that taking phytoestrogens containing isoflavones from any source is safe to take if an estrogen-fed cancer is present. Other study assessing the action of isoflavones on rat endometrial cells reported that they did not stimulate cell proliferation.(66) The result was in line with that of human studies which showed no increase in endometrial thickness in postmenopausal women after supplementation of isoflavones. (67)



Cardiovascular effects - Isoflavones exert a wide range of effects on the vasculature, including: inhibition of endothelial cell proliferation; inhibition of chemotaxis and proliferation of vascular smooth muscle cells; promotion of whole cell calcium-activated potassium-channel currents in vascular endothelial cells; inhibition of platelet aggregation; and vasodilation and inhibition of thrombin-evoked calcium entry into smooth muscle cells. (43) , (44) Isoflavones also inhibit nitric oxide production by macrophages and the pro-coagulant activity of activated adherent monocytes. (45) , (46)

Though debated, isoflavones have been reported to decrease serum lipids in vivo and in vitro. (47) A proprietary extract of red clover has been reported to raise HDL cholesterol and decrease ApoB. (48) Authors reported that supplementation with isoflavones did not significantly alter total plasma cholesterol, LDL cholesterol, HDL cholesterol or plasma triglyceride levels levels (49), while others showed a reduction in total cholesterol, LDL cholesterol and triglycerides and an increase in HDL levels. (52) , (68) , (69) Regardless of the impact red clover has on serum lipids, Nestel PJ, et al. suggest that red clover isoflavones reduce cardiovascular risks by reducing arterial elasticity in menopausal women, not by altering serum lipids to any significant extent. (50) Another study evaluated the impact of isoflavones derived from red clover on arterial compliance in 17 women. After a run-in period, a 5-week placebo period was followed by a 5-week period of active treatment with 40 mg of isoflavones and then a 5-week period of active treatment with 80 mg isoflavones. Arterial compliance rose by 23% with the 80-mg isoflavone dose compared to the placebo period. The increase was slightly less with the 40-mg dose. (51)

A meta-analysis on clinical trials reported that red clover isoflavones supplementation produced a marginal significant effect in treating hot flushes symptom. (70) However, this result is in contrast with another systematic review and meta-analysis which reported no significant reduction in hot flushes frequency. (71) The authors suggest that a large placebo response and inadvertent use of dietary isoflavones in the placebo group may have obscured a significant change in flushing frequency. Recently, isoflavones was shown to reduce anxiety and depressive symptoms among postmenopausal women. (72)

Neuroprotective effect (in vitro)- Isoflavones exert neuroprotective effect on human cortical neurons from glutamate toxicity, probably due to their antioxidant and oestrogenic properties. (73) They also protected dopaminergic neurons from lipopolysaccharide-induced damage by inhibiting microglia activation and generation of pro-inflammatory factors.(74) , (75)

The liquid extract of red clover has traditionally been used as an alterative, or as stated above, an agent that "purifies" the blood, removing toxins and improving liver and kidney function, and helping the body maintain homeostasis. (53) Red clover liquid extracts were used routinely by early Eclectic Physicians in conditions such as spasmodic coughs and cancer.

References

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