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Clover and Menopause
By David Kiefer, MD. Dr. Kiefer is a Clinical Instructor, Family Medicine, University of Washington, Seattle; Clinical Assistant Professor of Medicine, University of Arizona, Tucson; and Adjunct Faculty at Bastyr University, Seattle. Dr. Kiefer reports no financial relationships to this field of study. This article was originally published in the August 2009 issue of Alternative Medicine Alert.
Recent reports of hormone replacement risks aren't making menopause any easier. Many women suffering from hot flushes, insomnia, loss of libido and memory, and other problems related to menopause, now find themselves in the lurch, unsure what safe treatments are available to them. Clinical trials have been performed that focus on herbal medicines and their effects on symptoms of menopause such as black cohosh (Actaea racemosa) and soy (Glycine max). This review will add another plant, red clover (Trifolium pratense), to our knowledge base on the subject. Read on to find out that red clover has more relevance to our lives than just searching for the four-leaved clover in a field of wildflowers.
History and Traditional Use
Red clover has a long history of traditional use throughout the world, most commonly for its respiratory and purported anticancer effects.1 In North America, the Cherokee, Ute, and Iroquois documented many medicinal uses for red clover,1 while in Ayurvedic medicine it is used to decrease excessive pitta and kapha doshas while heavily increasing the vata dosha.2 In traditional Chinese medicine, red clover is utilized for its effects on the liver, heart, and lung meridians.3
Modern herbalists use red clover for childhood eczema, psoriasis, coughs, bronchitis, and whooping cough.4 The herb has also been shown to be helpful with pharyngeal inflammation and salivary congestion, and may have antibacterial activities, in addition to being part of the Hoxsey anticancer formula.4,5
The estrogenic effects of red clover, and its isoflavones, began to be investigated after observations of breeding effects and changes in the estrous cycles of livestock known to be grazing on large amounts of red clover.1
Botany and Pharmacology
Red clover (Trifolium pratense) is in the bean family (Fabaceae) and was named by Carolus Linnaeus in 1753; pratense translates from Latin to "found in meadows." This species of Trifolium is native to Northwest Africa, Europe, and Western Asia, and is a herbaceous perennial, growing to approximately 1-3 feet in height. The leaves consist of three leaflets ("three-leaved clover"); it is most commonly the pale violet-colored flowers that are used medicinally.
Red clover contains many phytochemicals, but especially relevant to menopause are the isoflavones, flavones, and flavonols.1,6 Red clover contains the same isoflavones as soy, though in different concentrations; it contains a higher concentration of biochanin A and formononetin than genistein and daidzein, the reverse of the proportion of these compounds found in soy.1,7,8 In addition to the fact that red clover supplements do not contain the proteins present in soy products, these unique phytochemical profiles are the main difference between the two plants with respect to menopausal effects.1
There are other constituents in red clover that may have physiological effects. For example, the polysaccharides present may provide antitumor activity by increasing the chemotactic markers that signal granulocytic leukocytes.4 Red clover also contains coumarins, volatile oils (furfural), clovamides, and other flavonoids including pectolinarin and kaempferol.4
Mechanism of Action
There are numerous postulated mechanisms for the method by which red clover might improve hot flushes and other symptoms of menopause. The exact mechanism of action of the isoflavone phytoestrogens in red clover is still being elucidated but appears to involve, like soy, a combination of agonism and antagonism with respect to estrogen receptors.9,10 There is also some evidence for a direct central estrogenic effect on hypothalmic thermoregulators, further supported by lower serum follicle-stimulating hormone (FSH) levels correlating with fewer hot flushes in some studies.11 Related to these purported effects, there are conflicting data in the medical literature regarding the effect of phytoestrogens on serum estrogen and gonadotrophin levels; some results show increases, others decreases or no changes.12
There are numerous reviews that have examined herbal medicines, including red clover, being used for menopause.9,10,13,-15 For example, a review through March 2007 of numerous non-hormonal therapies for menopause found six studies for red clover.10 The researchers concluded that there was an inadequate number of Level 1 studies, the effects were inconsistent when compared with placebo groups, and long-term safety was unknown.
In addition, a group of clinical trials have examined the efficacy of herbal products containing more than one herb to treat symptoms of menopause.16 Results from this research are interesting from the standpoint that it is helpful to know whether a specific product works and/or is safe, but it remains then to figure out which individual component or combination of components is actually responsible for the effect(s).
Other papers1,17 have reviewed some of the existing clinical trials on red clover for symptoms of menopause;12,18-22 the main clinical outcomes examined were the number and severity of hot flushes. A meta-analysis of five of these trials (all using the proprietary extract Promensilâ) found that the red clover groups had 1.45 fewer hot flushes per day than the placebo groups (P < 0.05).17 In the other review, of seven clinical trials examined, four found no changes in hot flushes.1 The trials, again using Promensil, varied with respect to length of study (2-12 months), total isoflavone content used (40-160 mg daily), and numbers of women included in the study (30-252). One example of the "positive" studies randomized 30 women with at least five hot flushes daily to either 80 mg isoflavones per day (Promensil) or placebo for 12 weeks, after a four-week placebo run-in period, and showed a 44% decrease in hot flush frequency (P < 0.001).22 The authors point to the higher isoflavone dose, the more severe hot flush entry criteria, and the run-in period as reasons why a significant effect was seen in this study but not other Promensil trials.
Red clover researchers have commented that positive effects of red clover in menopausal symptoms may not appear before eight weeks of treatment and may require more than the 40 mg daily total isoflavones used in many studies.1 Furthermore, future research should take into account the contribution of other important variables, such as the isoflavones in the background diets of study subjects, to more accurately comment on the effects of phytoestrogen supplements.
Other women's health effects have been documented in clinical trials of red clover. For example, research has examined the effects of red clover on characteristics of the vaginal mucosa, overall sexual health, and hormone levels.7,11,22 One randomized trial compared 109 women receiving either two capsules of a standardized red clover extract (MM11RCE, 80 mg of isoflavones) to placebo for three months, and found that the red clover group had increased serum testosterone (P < 0.001), decreased endometrium thickness (P < 0.001), and no change in serum estradiol.7 Also, a crossover trial randomized 60 postmenopausal women to receive either red clover (the proprietary extract Menoflavon, 80 mg isoflavones daily) or placebo for three months.11 Only 49 women completed the trial that resulted in a statistically significant drop in the total Kupperman index (a compilation of numerous menopausal symptoms each rated from 0 [not present] to 3 [severe]) from a baseline of 27.2 to 5.9 in the isoflavone group vs 20.9 in the placebo group (P < 0.05). In addition, the red clover group had positive effects on vaginal cytology, and a slightly lower serum triglyceride level. Finally, an extract of red clover (MF11RCE, 80 mg of isoflavones daily) over 90 days helped 53 postmenopausal women with vaginal and sexual health issues by improving the vaginal cells' karyopyknotic, cornification, and basal cell maturation indices, decreasing vaginal dryness, decreasing dyspareunia, and improving libido.22
Dosage and Administration
Promensil is one product used in clinical trials, often dosed as a 40-80 mg tablet daily, providing 3.24-6.48 mg of isoflavones daily; Rimostil, on the other hand, is usually dosed 57 mg daily, providing 13.11 mg isoflavones daily.1,6 As a comparison, the USP reference dose is a 50 mg tablet containing 6.60 mg of isoflavones;6 of note, most clinical trials (see "Clinical Trials" section) refer to the tablet-mg amounts as "isoflavones," a different quantity from the laboratory-extracted amount.6
There is a wide variety in isoflavone content in both the products available for purchase and those that have been studied in research trials. Researchers have found a range of daily doses being recommended that correspond to daily isoflavone intakes of 4-43 mg, which may or may not correspond with what laboratory testing actually determines is present in the product.1,6 There can also be varying ratios of the four main isoflavones and different plant parts (flowers, above-ground parts, leaves, and/or whole plant) used to make the extracts.1,6
Adverse Effects and Drug Interactions
Some references are made to adverse effects in clinical trials. In one review, only three of 17 articles mentioned adverse effects, all of which were mild (such as headache, thrush, upper respiratory tract infection, nausea, and diarrhea).17 Other reviews and clinical trials list a variety of similar mild, self-limiting complaints.
Many researchers have explored a possible increased breast cancer risk with the use of phytoestrogens. There seems to be a mix of enhanced proliferation, anti-proliferation, tumor prevention, and complicated estrogen and progesterone-receptor binding at work, depending on the specific phytoestrogen being tested and the type of in vitro and in vivo model.14 Some clinical trials have actually demonstrated decreased endometrial thickness in the red clover treatment groups,1,7 though a five-year study of 376 women using 150 mg of soy isoflavones or placebo daily demonstrated less endometrial atrophy (70% vs 81% in the placebo group) and 3.8% had endometrial hyperplasia (vs 0% in the placebo group; P < 0.05).23 Examining possible effects on breast tissue, one research group randomized 205 women to one tablet of Promensil or placebo daily for one year, showing no significant differences between the groups with respect to mammographic appearance (i.e., breast density) of breast tissue.12 In addition, in the latter study, red clover did not significantly affect serum estradiol, FSH, or luteinizing hormone.
Red clover has been shown to cause in vivo inhibition of thyroid peroxidase, and the liver cytochromes, CYP1A1, CYP1B1, and CYP2C9, though no clinically significant adverse effects related to any of these has yet been observed.1
Red clover, a member of the bean family, has been a medicinal favorite across the centuries and across the continents. It is most well known now for its isoflavones, especially biochanin A and formononetin, and resulting phytoestrogenic effects and, therefore, potential benefits for symptoms of menopause. The exact physiological effect of these phytoestrogens is complicated and still being determined, but seems to have both agonist and antagonist effects on central hypothalamic and distal estrogen receptors. Result of clinical trials have been mixed, with many showing no benefits when compared to placebo; it is possible that doses on the higher end (for example, > 6 mg isoflavones daily), and for at least eight weeks, are more likely to be effective at lowering the number of hot flushes daily or other menopausal symptoms. Recommended doses vary; each proprietary extract contains certain plant parts in certain concentrations, invariably changing the phytochemical profile. It may be best to aim for doses comparable to the USP standard of 50 mg of red clover containing 6 mg isoflavones daily. Adverse effects are generally mild as noted in clinical trials, and other, more severe adverse effects, such as increased breast tissue density and resulting risk of breast cancer or endometrial hyperplasia, appear to be primarily theoretical in nature. Definitive, large clinical trials remain to be done to answer these questions for sure.
There are many unknowns about the use of red clover for menopause. Its efficacy in clinical trials is variable, and each proprietary extract varies in the spectrum of isoflavones. Furthermore, there are concerns, just as with conventional hormone therapy, about the risk of breast and endometrial cancer; there are some preliminary results for red clover that are reassuring, but these need to be replicated. Provided that a woman is not at high risk for breast cancer nor a breast cancer survivor, red clover could be considered as one option for the treatment of hot flushes and other symptoms of menopause; if so, doses on the higher end for proprietary extracts used in clinical trials (for example, Promensil 80 mg daily or Rimostil 57 mg daily) should be used for at least 8 weeks.
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