What is red clover

Red clover (Trifolium pratense L) is a high-quality fodder crop belonging to the family of plants called legumes (just like peas and beans) that is widely cultivated in most temperate regions both within Europe and worldwide. Red clover is sown as a companion crop and a green manure crop to increase soil fertility ¹. Red clover is the second most widely grown forage legume in the United States, after alfalfa, and is considered a high-value feed for livestock because of its digestibility, and protein content ². Being a nitrogen-fixing forage crop, red clover has a great potential in sustainable agriculture ³. Red Clover is also widely used as a herbal supplement for the reduction of menopausal symptoms, as an alternative to the conventional hormonal replacement therapy, because Red clover contains phytoestrogens called isoflavones—compounds similar to the female hormone estrogen. Red clover extract isoflavones are metabolized to genistein and daidzein after consumption. Potential adverse effects of phytoestrogens have included deficits in sexual behaviour in rats and impaired fertility in livestock (Bennetts 1946). No specific examples of toxicity among humans have been noted in countries in which soy is consumed regularly ⁴. It is generally considered difficult for humans to consume the quantity of isoflavones from natural soy foods needed to reach toxicological levels that induce pathological effects, as recorded in animals. Asian people consume more isoflavones from their regular diet than Western people. Daily isoflavones intake in Chinese and Japanese people was estimated to be 15 to 50 mg/day ⁵, whereas it was likely to be less than 3 mg/day in European and US populations ⁶.

In folk medicine, red clover was used for a variety of conditions including asthma, whooping cough, cancer, and gout. Today, isoflavone extracts from red clover are most often used as dietary supplements for menopausal symptoms, high cholesterol, or osteoporosis. The flowering tops of the red clover plant are used to prepare extracts available in tablets or capsules, as well as in teas and liquid forms.

What scientists know about red clover

• Red clover has not been clearly shown to be helpful for any health condition.
• Most research indicates that taking red clover does not relieve menopause symptoms such as hot flashes.
• A 2015 meta-analysis and systematic review of 15 randomized controlled trials ⁷ found no significant treatment effect of phytoestrogen on menopausal symptoms as compared with placebo. However, an analysis of the ten studies that reported hot flash data indicated that phytoestrogens result in a significantly greater reduction in frequency of hot flashes compared to placebo.
• A 2014 systematic review ⁸ concluded that studies of isoflavones had significant reductions on hot flashes and co-occurring symptoms during menopause and post-menopause, but replication of studies with larger sample sizes are needed.
• A 2013 Cochrane review ⁹ of 43 randomized controlled trials involving a total of 4,084 participants with hot flashes found some trials reported a slight reduction in hot flashes and night sweats with phytoestrogen-based treatment; however many of the trials included in the review were small, of short duration and of poor quality. The phytoestrogens containing high levels of genistein (a substance derived from soy) appeared to reduce the number of daily hot flashes, but needs to be further investigated. Overall, there was no indication suggesting that other types of phytoestrogens work any better than no treatment.
• Because red clover contains estrogen-like compounds, there’s a possibility that long-term use would increase the risk of women developing cancer of the endometrium (the lining of the uterus). However, short-term studies of women who have taken red clover have not shown harmful changes in the uterine lining.
• Red clover may not be safe for women who are pregnant or breastfeeding, for children, or for women who have breast cancer or other hormone-sensitive cancers.
• Red clover supplementation is not advised in children younger than 12 years.
• The main chemical classes contained in red clover are carbohydrates, isoflavones, flavonins, and saponins. Other constituents include coumaric acid, fats, minerals, and vitamins. A volatile oil that includes methyl salicylate is distilled from the flowers ¹⁰. Isoflavones are often termed phytoestrogens because of their functional similarity to estrogens. The major isoflavones in red clover are biochanin A, formononetin, daidzein, and genistein; total phytoestrogen content is approximately 0.17%.
• Clinical practice guidelines issued in 2011 by the American Association of Clinical Endocrinologists ¹¹ for the diagnosis and management of menopause state that phytoestrogens, including soy-derived isoflavonoids, result in inconsistent relief of symptoms. The guidelines advise that women with a personal or strong family history of hormone-dependent cancers, thromboembolic events, or cardiovascular events should not use soy-based therapies. Likewise, guidelines from the American College of Obstetricians and Gynecologists state that phytoestrogens and herbal supplements have not been shown to be useful for treating hot flashes.

The red clover plant is low and bushy with several hairy stems arising from a taproot. Dense terminal heads of up to 125 fragrant red-to-purple flowers are borne at the end of the branched stems. The leaves occur in groups of 3 ovate leaflets; a characteristic lighter water mark in the shape of an inverted V is visible at the center of the group.

Figure 1. Red clover (Trifolium pratense L.)

Red clover traditional medicine uses

Dried red clover flowers have been used in traditional medicine to treat a wide variety of ailments, including jaundice, cancer, breast tissue infections, joint disorders, and respiratory conditions (e.g, whooping cough, bronchial asthma), and as a sedative. The plant was thought to purify the blood by promoting urine and mucus production, improving circulation, and stimulating secretion of bile. Red clover ointments have been used topically to speed wound healing and to treat psoriasis, eczema, and rashes. Respiratory complaints have been treated with an infusion; poultices of the whole plant have been used as topical applications for cancerous growths.

However, there is no clinical evidence to support any of these uses. Safety of use in treating breast cancer has not been determined, and protection against prostate cancer has not yet been confirmed by clinical trials.

Red clover health benefits

There have been several studies of red clover in people, but their results haven’t provided clear evidence of any beneficial effects.

Red clover flowers have been used traditionally as a sedative, to purify the blood, and to treat respiratory conditions; topical preparations have been used for psoriasis, eczema, and rashes, and to accelerate wound healing. More recently, clinical trials have been conducted examining red clover’s use in the treatment of menopausal symptoms, but with minimal to no possible effects. A few additional studies have shown positive effects on cardiovascular health and bone density, although they have included only a small number of subjects.

Much of the interest in red clover originated from observations of positive health benefits derived from the use of soy products. Both soy and red clover are sources of isoflavones and have similar estrogenic activity; in test tube studies have shown this to be approximately 1/400th that of 17-β-estradiol ¹².

Red clover for menopause

According to the North American Menopause Society ¹³, in five controlled studies, no consistent or conclusive evidence was found that red clover leaf extract reduces hot flashes. As with black cohosh, however, some women claim that red clover has helped them ¹³. Studies report few side effects and no serious health problems with use. But studies in animals have raised concerns that red clover might have harmful effects on hormone-sensitive tissue.

A wide range of products containing plant or phytoestrogens, including soy products, are available as over the counter remedies for hot flushes. Studies have varied widely in the dose and nature of compounds tested and the active product of these is thought to be isoflavones. Varied outcomes have been demonstrated with some short term studies suggesting that there may be some benefit in using these products early in menopause but we are still lacking good long term studies. The available evidence suggests that isoflavones do not relieve long term menopausal vasomotor symptoms any better than placebo ¹⁴.

There is some evidence that questions the safety of these products in patients with breast cancer and phytoestrogen supplements may interfere with treatments for breast cancer ¹⁵.

Cardiovascular effects

Beneficial effects of soy protein on blood lipid profiles have been demonstrated. However, results from studies of red clover have been mixed, with either no effects on plasma lipids ¹⁶ or with only modest improvements observed ¹⁷. Results from studies investigating vascular effects of red clover have been more encouraging.

No improvements in cardiovascular risk factors were associated with the 1-year use of a red clover-derived isoflavone supplement by women aged 49 to 65 years. However, a trend toward potentially beneficial changes in triglycerides was observed in perimenopausal women ¹⁷. A small but significant decrease in triglyceride levels was observed in another study of women receiving Promensil or Rimostil . Women with elevated baseline triglyceride levels showed greatest improvement ¹⁸. However, the effect was probably too small to be clinically important. These studies suggest that isoflavones may not be responsible for the well-documented effects of soy protein on blood lipids.

Arterial compliance, an index of the elasticity of large arteries, improved in a small, short-term study of postmenopausal women receiving Promensil ¹⁹. These results were confirmed by a larger study of normotensive men and postmenopausal women ²⁰. Ambulatory blood pressure remained unchanged but total peripheral resistance improved in these patients. Subjects received 80 mg/day of a red clover-derived isoflavone supplement containing mostly biochanin A or formononetin; improvements were greatest in the formononetin group.

Effects on bone density

Diets rich in soy protein have been associated with reduced incidence of hip fracture and attenuation of bone loss. Because of this, red clover has been investigated also.

Isoflavone supplementation was associated with reduced losses of bone mineral content and bone mineral density at the lumbar spine in a large study (N = 205) ²¹. Markers of bone formation were also increased in women, 49 to 65 years of age, who received Promensil for 12 months. Postmenopausal women appeared to gain most advantage. Between-group differences in bone mineral density at the hip were not significant. Another trial showed no differences in markers of bone turnover among menopausal women receiving Rimostil, Promensil, or placebo ¹⁸. However, the validity of the results may have been affected by the short study duration (12 weeks).

Other uses

Biochanin A has been reported to inhibit carcinogenic activity in cell cultures ¹⁰. Men with low- to moderate-grade prostate carcinoma who received isoflavonoid supplements prior to radical prostatectomy showed no changes in serum prostate-specific antigen, serum testosterone, or biochemical factors ²¹. However, analysis of prostatectomy specimens showed an increase in apoptosis, particularly in regions of low- to moderate-grade cancer, when compared with historical controls.

Red clover dosage

The traditional dose of red clover blossoms for sedation is 4 grams. Red clover is now used primarily as a source of isoflavones. The usual dose is 40 to 80 mg/day of standardized isoflavones, typically containing biochanin A, formononetin, genistein, and daidzein. Several commercial preparations are available.

Extracts standardized for isoflavone content (eg, Promensil and Rimostil ; Novogen Laboratories , North Sydney, Australia) have been used frequently in clinical trials. These tablets contain biochanin A, formononetin, genistein, and daidzein; Promensil contains a higher proportion of biochanin A and genistein and lower proportions of formononetin and daidzein than Rimostil ²². The usual dosage is 40 to 80 mg/day of total isoflavones (1 to 2 tablets).

Red clover side effects

No serious side effects have been reported in studies that evaluated red clover for various health conditions for up to a year. High doses of isoflavones have been associated with loss of appetite, pedal edema, and abdominal tenderness.

The role of clover species in causing intracranial hemorrhage has been known since the 1920s with the discovery of sweet clover hemorrhagic syndrome in cattle which proved to be the first step in the development of warfarin. In addition to coumarin derivates, Red Clover contains phenolic compounds which inhibit platelet adhesion and reduce platelet factor 4 release ²³. The literature contains one case of intracranial bleeding due to Red Clover where a patient suffered a spontaneous, nonaneurysmal subarachnoid hemorrhage ²⁴. In another case a 65-year-old woman who suffered a spontaneous acute-on-chronic subdural hemorrhage with a significant postoperative re-hemorrhage after taking Red Clover supplements for her postmenopausal symptoms ²⁵. Further questioning into her history revealed that she had been taking Red Clover for the preceding 8–10 years (364 mg per day of standardized Red Clover extract containing 40 mg isoflavones, as recommended by the manufacturer) as an over-the-counter herbal preparation for relief of menopausal symptoms. These cases highlight another risk factor for intracranial hemorrhage and the mechanism of Red Clover induced coagulopathy appears to be mediated through anti-platelet actions, assumed to be due to the coumarin derivatives, hence the contraindication for Red Clover use alongside warfarin; however, in-vitro evidence has shown Red Clover’s role in preventing platelet adhesion ²⁶.

Contraindications

Red Clover is contraindicated in patients with a history of breast cancer and during pregnancy or lactation.

The phytoestrogens in red clover may be expected to act through estrogenic mechanisms with the associated risk of estrogen-like adverse effects, including increased incidence of endometrial, ovarian, and breast cancers.

The finding from a 2015 systematic review and meta-analysis suggests that red clover consumption may have breast cancer-promoting effects ²⁷. An earlier 2002 meta-analysis showed a positive relationship between levels of estradiol and increased risk of breast cancer ²⁸. The 2015 systematic review and meta-analysis study showed that red clover may increase the risk of estrogen-dependent cancers as estradiol showed a borderline increase in the red clover groups in comparison with control group base on three trials ²⁷.

Pregnancy/Lactation

Red clover has estrogenic activity. Avoid use.

Interactions

Isoflavonoids may interfere with hormonal agents; avoid use with oral contraceptives, estrogen, or progesterone therapies.

Red clover contains coumarin derivatives; there is little risk of anticoagulant abnormalities ²⁶.

Toxicology

The phytoestrogens in red clover may be expected to act through estrogenic mechanisms with the associated risk of estrogen-like adverse effects, including increased incidence of endometrial, ovarian, and breast cancers. Red clover induced a proliferation of estrogen-sensitive breast cancer cells in an in vitro study ²⁹. However, another study showed that mammographic breast density, a marker for estrogenic and antiestrogenic effects, was unaffected by administration of Promensil for 1 year in women 49 to 65 years of age ³⁰. A small pilot study found no antiproliferative effects on the endometrium associated with use of red clover isoflavones ³¹. Three trials ³², ³³, ³⁴, assessed the effect of red clover on the endometrial thickness. Overall, it seems that red clove showed a range of null effect to non-significant decrease in postmenopausal period. However, further studies with control group are required to confirm this data.

Infertility and growth disorders have been observed in grazing animals receiving high proportions of red clover in their feed. This has been attributed to the estrogenic activity of red clover. A syndrome characterized by infertility, abnormal lactation, dystonia, and prolapsed uterus, known as clover disease, has been described in sheep.

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