Red Clover for the Treatment of Menopausal Symptoms and Hyperlipidemia

By Melinda Ring, MD, and Marjorie Alschuler, PhD

In the united states, nearly 85% of menopausal women complain of hot flashes, and 35% seek medical attention for it.1 And although it’s estimated that fewer than 40% of U.S. menopausal women start hormone replacement therapy (HRT), only 15% take it for long.2 Reasons cited include fear of breast cancer, desire for "natural" remedies, dislike of side effects, such as breast tenderness and vaginal bleeding, and known contraindications.3

Phytoestrogens, particularly those in soy products, have been in the spotlight as a serious contender for an HRT replacement ever since epidemiological studies showed an association with a lower incidence of hot flashes, cardiovascular disease, and cancers. Red clover (Trifolium pratense) is an herb-derived phytoestrogen, which is popular among women who desire an alternative treatment to combat the effects of estrogen deprivation.

Goals of Management

The medical management of menopause has two goals: 1) alleviation of undesirable symptoms and 2) prevention of resultant diseases, which lead to morbidity in later years.

Clinical Trials of HRT in Menopausal Women

Recent large-scale studies such as the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women’s Health Initiative have provided evidence that cardiovascular risks associated with HRT may outweigh the benefits in some groups of women.4

The two indications for which HRT does have proven efficacy are symptom management: reducing hot flashes by up to 90%, and preventing bone density loss, with a 50-60% reduction in fractures.5

New guidelines, reflecting the shifting risk:benefit ratio, suggest that HRT be restricted to short-term use (less than five years) for management of vasomotor symptoms, with long-term use only in those patients at high risk for osteoporosis.4

Red Clover Pharmacology

Phytoestrogens are naturally occurring substances found in plants that are structurally or functionally similar to estradiol (E2).

Phytoestrogens have been called natural selective estrogen-receptor modulators, or SERMs.6 Depending on the concentration of endogenous estradiol and the distribution of estrogen receptors, they may act as either an estrogen receptor (ER) agonist or as an estrogen antagonist. Estradiol binds the receptor with higher affinity than the isoflavones, but when either binds the ER, the receptor undergoes homodimerization, and then can bind specific regions of DNA to regulate gene transcription.

The three main classes of phytoestrogens are isoflavones, coumestans, and lignans. High concentrations of isoflavones are found in legumes such as soybean and chickpea, and herbs like red clover and bluegrass. While soybeans contain the two major isoflavones genistein and daidzein, red clover also contains biochanin A and formononetin. Of these four iso-flavones, genistein has the greatest bioactivity.7

Clinical Trials

Hot flashes. Novogen Ltd., the distributor of the red clover extract Promensil, recently sponsored two double-blind, placebo-controlled trials examining the extract’s effect on menopausal symptoms.

The first study by Baber et al included 51 women (ages 45-65 years) amenorrheic for at least six months with a minimum of three hot flashes daily.8 Data collection included serum tests, urine isoflavone analyses (to monitor compliance), transvaginal ultrasounds (for endometrial thickness), vaginal smears (for vaginal maturity index), symptom logs, and serial measurements on the Greene menopause symptom scale. The trial had four phases: one-week run-in; 12-week treatment (active or placebo); four-week placebo washout; and crossover to the alternative treatment regimen for 14 weeks. Forty-three subjects completed all four phases. No statistically significant difference was found between the active and placebo groups on any of the measured parameters.

The second study by Knight et al randomized 37 women (ages 40-65 years) to a 12-week course of placebo, Promensil 40 mg total isoflavone, or 160 mg extract total isoflavone.9 Inclusion criteria and modes of assessment were similar. Once again, all groups experienced a decrease in hot flash frequency (35%, 29%, 34%, respectively) with no significant difference between them. The analysis of urine isoflavone levels at week 0 and week 12 showed the expected increases in the Promensil groups, but also showed a small increase in the placebo group. The authors suggest that this rise might have resulted from the inadvertent ingestion of soy products by members of the placebo group, which in turn may have affected the number of hot flashes.

In 1999, two groups at the International Menopause Society World Congress reported reductions in hot flash frequency ranging from 56% to 75% with Promensil 40 mg compared to placebo, but these results have only been published in abstract form.10,11

Cardiovascular-lipids. Soy proteins, like HRT, have been shown to counteract partially the unfavorable change in the lipoprotein profile that develops after menopause.12 Potential mechanisms include an upregulation of low-density lipoprotein (LDL) receptors and increased turnover of LDL-apolipoproteins. Studies examining red clover isoflavones and lipid homeostasis have conflicting results, and are compromised by differing isoflavone compositions, inadequate blinding or randomization, lack of a control group, and poor completion records.

Improvements in the lipoprotein profile were noted in a recent study by Clifton-Bligh et al.13 Three doses of a red clover extract Rimostil (28.5 mg, 57 mg, and 85.5 mg daily) were administered to 46 postmenopausal women for six months in a double-blind protocol. Non-fasting measurements showed a significant rise in high-density lipoprotein (HDL) of 15.7-28.6% and a decrease in apolipoprotein B of 11.5-17% after six months, although the changes were independent of the doses given. The aforementioned study by Knight et al also reported an increase in HDL by 18% in participants taking 40 mg dose of isoflavones compared to placebo; this increase was not observed in those participants taking the 160 mg dose.

In contrast, Howes et al gave 93 postmenopausal women either placebo or isoflavone extract (approximately 43.5 mg for five weeks, then 88 mg for five weeks).14 Baseline lipids were 5-9 mmol/L. Seventy-five women completed the study (66 active group, nine control); the reasons for drop-out were not cited. No significant changes were noted in total cholesterol, HDL, LDL, or triglycerides in either group. Nestel and colleagues examined lipid profiles throughout their trial; no significant changes were observed.15 Lastly, 14 of 21 premenopausal women completed a single-blind randomized trial with a crossover of red clover extract (86 mg) and placebo for two months each.16 Again, no alteration in total cholesterol, triglycerides, or LDL oxidizability was identified.

Bone. The previously mentioned trial by Clifton-Bligh et al also measured bone density of the proximal radius and ulna. Increases were found with the 57 mg and 85.5 mg doses (4.1% and 3%, respectively), but not with the 28.5 mg dose.13 Another trial published in abstract form only enrolled 107 women (pre-, peri- and post-menopausal women) ages 50-64 years.17 Promensil 40 mg daily or placebo was given for almost a year. The preliminary results showed a decrease in lumbar spine density in the placebo group greater than that of the Promensil group. No difference in hip density was seen.

Formulations

Red clover is available in many preparations such as teas and liquid extracts, but is most commonly taken as an extract in tablet form. It is dosed according to the isoflavone content, with 40 mg/d in most standardized formulations. Consumers and practitioners prescribing red clover need to be aware of labeling variations. "Isoflavone content" may refer to the amount of the estrogen-like compounds (genistein, daidzein, biochanin A, and formononetin) alone, or may include linked sugar moieties (i.e., isoflavone glycosides).

In December 2000, Consumerlab.com performed independent quality-control tests on six red clover isoflavone products (two red clover alone, four red clover/soy combinations). Half of the products failed testing, as they contained only 50-80% of the claimed amount of isoflavones. The three products that received passing scores were Promensil (Novogen Inc.), PhytoFem (Shaklee Corp), and Red Clover Support Complex (Vitamin World Inc.).

Adverse Effects/Drug Interactions/ Contraindications

Reproductive-endocrine system. Reproductive disorders were noted in grazing animals ingesting large amounts of clover. The amounts ingested, however, were far beyond those intended for human consumption.18 Because of the estrogen-like activity of red clover, it is recommended that pregnant and lactating women avoid red clover. It also should not be taken by women already receiving any form of hormone treatment, including estrogens, progesterones, or androgens.

Uterine effects. Of the trials reviewed, the three that studied endometrial thickness by ultrasound found no evidence of hyperplasia.8,10,13 A recent pilot study postulated that isoflavones might be antiproliferative and protect against endometrial cancer.19 Perimenopausal women underwent endometrial biopsy with measurement of an antiproliferative marker and ultrasound with Doppler before and after three months of extract or placebo. Again, no change was noted.

Breast tissue. Unraveling how isoflavones affect breast tissue is a difficult task.20 Human studies are difficult to perform, and without knowing intramammary concentrations of estradiol and isoflavone one cannot determine whether the interaction will inhibit cell proliferation (by competitive inhibition of ER binding or inhibition of tyrosine kinase of growth factor receptors) or stimulate cell proliferation (if E2 levels are low).

Bleeding parameters. The presence of coumarin in some clover species may potentiate the anticoagulant effect of medications, although no documented cases of an interaction exist.21

Ongoing Research

In an effort to address the growing pressure to find alternatives for women, the NCCAM/NIH awarded a five-year, $7.7 million grant to the University of Illinois at Chicago (UIC) to study menopausal symptoms. Two ongoing UIC studies focus on red clover and black cohosh (another herb used for menopausal symptoms). The aim of this toxicity study of six dosages is to determine active ingredients, modes of action, and metabolism, followed by a year-long double-blind clinical trial to study efficacy in symptom relief and disease prevention.

Conclusion

The current evidence does not support the use of red clover for symptom alleviation or preventive care in postmenopausal women. Although no serious side-effects have been reported yet, research trials of inadequate duration and power exist.

Recommendation

Patients seeking relief from perimenopausal vasomotor symptoms should be advised that red clover appears to be inferior to HRT and other herbal remedies such as black cohosh. Similarly, diet and exercise recommendations will be more beneficial than red clover to maintain cardiovascular and bone health in postmenopausal women. The results of the NIH-supported study at UIC should help elucidate the role of red clover and other remedies.

Pregnant and lactating women and women taking hormone replacement therapy or androgens should avoid red clover, as should breast cancer survivors. Close attention should be paid to bleeding parameters and symptoms when other women take red clover with warfarin, heparin, aspirin, and dietary supplements with anticoagulant properties such as ginkgo, garlic, ginger, and vitamin E.

Dr. Alschuler is Medical Education Specialist, and Dr. Ring is Clinical Training Attending Physician and Coordinator, CAM Curriculum, Internal Medicine Residency Training Program, St. Joseph Hospital, Chicago, IL.

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