Considerable research has been carried out on the constituents of red clover. However, most of the investigations have been undertaken for agricultural rather than medicinal purposes. Very few investigations have concentrated specifically on the flower heads and the traditional uses.
RELIEF OF MENOPAUSAL SYMPTOMS
Although extracts standardised for soy isoflavone levels may help relieve symptoms, such as hot flushes and other symptoms frequently associated with menopause, the evidence from red clover isoflavones is less convincing.
A 2004 systematic review that included data from five trials published between 1966 until March 2004 concluded that phyto-oestrogens from red clover have not been shown to reduce hot flushes. The trials were placebo-controlled, involved a total of 400 women and tested a standardised red clover isoflavone extract available commercially as Promensil (Novogen Ltd, Sydney, NSW, Australia), which contains 40 mg isoflavones. Two of the smallest trials (n = 30 each) reported a significant decrease in hot flush frequency; however, three, double-blind placebo-controlled trials found little effect in reducing the incidence or severity of hot flushes. The largest and highest quality study involved 252 menopausal women, aged 45-60 years, who were experiencing at least 35 hot flushes per week. After a 2-week placebo run-in, participants were randomly assigned to Promensil (82 mg total isoflavones per day), Rimostil (57 mg total isoflavones per day) or a placebo. The reductions in mean daily hot flushes at 12 weeks were similar for all three groups. However, Promensil (but not Rimostil) reduced hot flushes more rapidly than placebo. Although the study provides some evidence for a biological effect of Promensil, neither supplement had a clinically important effect on hot flushes or other symptoms of menopause.
One study not included in this review was an American open study of 23 postmenopausal women (aged 40-65 years) suffering vasomotor hot flushes, which found that Promensil (standardised red clover isoflavone extract) containing 40 mg isoflavones taken daily for 2-3 months significantly reduced the self-rated intensity of hot flushes (P < 0.001). The mean endometrial thickness was unchanged and there was no significant change in the mean fasting total cholesterol, LDL, HDL, glucose, oestradiol, sex hormone binding globulin or FSH levels. There were no adverse effects.
Two new randomised studies have been published since the 2004 review. One was a double-blind placebo controlled trial of 60 menopausal women using 80 mg/day of red clover isoflavones for 90 days and they reported significant reductions in menopausal symptoms as compared to placebo and a positive effect on vaginal cytology. The other double-blind, placebo-controlled trial found no effects on breast density, oestradiol, FSH, LH or lymphocyte tyrosine kinase activity after 12 months of treatment with red clover isoflavones (43.5 mg/day) in 205 women aged between 49 and 65 years.
Because oestrogens have been reported to favourably alter lipid levels, there has been some investigation into the effects of red clover isoflavones in this regard. Currently, the evidence remains inconclusive and most studies report no significant effect.
In a double blind, placebo-controlled, randomised trial of red clover-derived isoflavones (43.5 mg/day), with 205 women aged between 49 and 65 years, active treatment had no significant effect on total cholesterol or HDL- and LDL-cholesterol levels or triglycerides. A single-blind, randomised crossover study of 21 healthy premenopausal women (aged 18-45 years) found that tablets containing 86 mg/day isoflavones for two menstrual cycles did not significantly change total cholesterol, HDL- or LDL-cholesterol or triglyceride levels. Another study of postmenopausal women with mild to moderate hypercholesterolaemia also found red clover did not significantly affect plasma lipids. A recent double-blind, randomised parallel study found that 86 mg/day purified isoflavones derived from red clover also had no effect on cholesterol homeostasis or insulin resistance in 25 premenopausal women.
However, there have been some positive findings. A randomised, placebo-controlled, crossover pilot study in 23 healthy pre- and postmenopausal women taking 86 mg/day isoflavones derived from red clover demonstrated an increase in HDL-cholesterol as compared to placebo after 1 month. A 12-week randomised, double-blind, placebo-controlled trial with 252 menopausal women investigated the possible benefits of isoflavones from red clover on cholesterol and triglyceride levels. Two products were investigated, Rimostil (57.2 mg total isoflavones) and Promensil (82 mg total isoflavones) and both extracts induced a statistically significant decrease in triglyceride levels. Additionally, a small but statistically insignificant increase in HDL-cholesterol was noted.
Blood pressure and endothelial function
Red clover isoflavones (approximately 50 mg/day) have been shown to favourably influence blood pressure and endothelial function in postmenopausal type 2 diabetic women in a randomised, double-blind crossover trial of 16 women. Mean daytime SBP and DBP were significantly lower during isoflavone therapy compared with placebo.
Alternatively, no effect on blood pressure was observed in a double-blind, placebo-controlled, randomised trial of red clover derived isoflavones (43.5 mg/day) in 205 women aged between 49 and 65 years.
Negative results were also seen in another study of healthy subjects (46 men, 34 women, age 45-75 years) who received isoflavones enriched in either biochanin or formononetin (precursors of genistein and daidzein; 80 mg/day) crossed over randomly with placebo in two 6-week periods. The red clover isoflavones reduced arterial stiffness and total vascular resistance, but had no effect on blood pressure. Previously, a double-blind, placebo-controlled trial of Promensil (40 mg and 80 mg) found that the isoflavone extract significantly improved arterial compliance compared with placebo. However, the large drop-out rate and poor study design means that the results are not compelling.
REDUCING CANCER RISK
Biochanin A, daidzein and genistein have demonstrated antiproliferative activity in vitro. Red clover isoflavones (50 mg total isoflavones), however, were found not to be antiproliferative in a double-blind randomised study of 30 perimenopausal women.
A non-randomised non-blinded trial of 38 men with clinically significant prostate cancer found that 160 mg/day red clover-derived dietary isoflavones, containing a mixture of genistein, daidzein, formononetin and biochanin A, significantly increased apoptosis compared with matched controls (P = 0.0018). There were no significant differences between pre- and post-treatment serum levels of prostate-specific antigen, testosterone or biochemical factors or Gleason score in the treated patients (P > 0.05). The study was performed in men undergoing radical prostatectomy; however, it indicates that the isoflavones may halt the progression of prostate cancer by inducing apoptosis in low to moderate-grade tumours (Gleason grade 1-3).
BENIGN PROSTATIC HYPERTROPHY
Isoflavone-containing supplements are widely used in patients with BPH. Recently, an in vivo study using mice showed that red clover-derived isoflavones have a significant effect on prostatic growth, and are capable of reducing the tendency to enlarged non-malignant prostate, by acting as anti-androgenic agents rather than weak oestrogenic substances. A case series (n = 29) presented at the Endocrine Society’s 82nd Annual Meeting in 2000 suggested that 3 months of treatment with 1 or 2 tablets of Trinovin (standardised to 40 mg red clover isoflavones per tablet) significantly decreased nocturia frequency, the International Prostate Symptom Score, increased urinary flow rates and QOL score. The PSA values and prostate size did not alter from baseline.
Pharmaceutical HRT is sometimes used for preventing loss of bone following menopause; however, a growing number of users are concerned about the increased risk of breast cancer associated with long-term HRT. As such, phyto-oestrogens have been used as an alternative to prevent osteoporosis. Most research has focused on soy isoflavones, although there is some evidence that red clover-derived isoflavones may also be of benefit.
In a recent trial by Atkinson et al, loss of lumbar spine bone mineral content and bone mineral density was significantly reduced in women taking red clover-derived isoflavones (43.5 mg/day) compared to placebo in a double-blind, placebo-controlled, randomised trial in 205 women over 12 months. Bone formation markers were also significantly increased; however, no improvement in hipbone mineral content or bone mineral density was noted. A double-blind study of 46 postmenopausal women investigated the effects of a red clover isoflavone preparation (Rimostil) containing genistein, daidzein, formononetin and biochanin A after a single-blind placebo phase and followed by a single-blind washout phase. Patients were randomly assigned to receive 28.5 mg, 57 mg or 85.5 mg phyto-oestrogens daily for a 6-month period. After the test period, the bone mineral density of the proximal radius and ulna rose significantly, by 4.1% with a dose of 57 mg/dayand by 3.0% with a dose of 85.5 mg/day isoflavones. The response with 28.5 mg/day isoflavones was not significant.
No significant difference in bone turnover markers was apparent after 12 weeks of treatment with Promensil and Rimostil in a double-blind, placebo-controlled, randomised clinical trial in 252 menopausal women aged between 45 and 60 years.
Red clover: Other Uses
Red clover flower heads are still used in the traditional manner for indications not related to the potential hormonal activity of the herb.
The British Herbal Pharmacopoeia lists red clover as a dermatological agent, mild antispasmodic and expectorant (British Herbal Medicine Association 1983). The specific indications are for eczema and psoriasis. Red clover is said to combine well with yellow dock for treatment of chronic skin disease.
Red clover: Dosage Range
• 4 g as infusion or extract.
• Liquid extract (1:1) in 25% alcohol: 1.5-3.0 mL/day.
• Concentrated isoflavone extract: extract containing 40-80 mg total isoflavones daily.
ACCORDING TO CLINICAL REPORTS
Menopausal symptoms: 40-82 mg daily of red clover-derived isoflavones.
Lipid-lowering: 40-86 mg daily of red clover-derived isoflavones.
Osteoporosis prevention: 44-86 mg daily of red clover-derived isoflavones.
BPH symptom relief: 40-80 mg daily of red clover-derived isoflavones.