t Clinical Studies References
Red clover is used for menopausal symptoms and hot flashes, cyclic breast pain or tenderness (mastalgia), cancer prevention, indigestion, whooping cough, cough, asthma and bronchitis.
The part used of red clover is the flower top. Red clover contains isoflavones, a class of phytoestrogens which are structurally similar to estrogens. In pre-menopausal women with normal endogenous estrogen levels isoflavones may have an anti-estrogen effect. In post-menopausal women with low endogenous estrogens, isoflavones are likely to act as weak estrogens. Isoflavones have a higher affinity for the beta estrogen receptor than the classical alpha estrogen receptor.
The beta estrogen receptor predominates in the heart, vasculature, bone and bladder, which may account for some of Red Clover's beneficial effects. Osteoporosis in post-menopausal women is related to declining estrogen levels. Red Clover is thought to be beneficial for preventing osteoporosis due to its weak estrogenic effects. Dietary phytoestrogens are associated with a reduced risk of endometrial cancer.
In cholesterol lowering treatment the estrogenic effects of red clover isoflavones might be involved in modulating lipid metabolism. Some researchers think Red Clover may play a role in preventing cardiovascular disease due to its potential effects on cholesterol levels.
Red Clover may be beneficial in cough, bronchitis, asthma, psoriasis, eczema, chronic skin diseases, menopausal symptoms (hot flashes, night sweats, reduced libido, vaginal dryness), improving cardiovascular risk factors (cholesterol levels, arterial compliance) and maintaining bone density (by reducing bone loss).
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Published Clinical Studiesctop
1 The potential for strategies using micronutrients and heterocyclic drugs to treat invasive gliomas.
Rooprai HK, Christidou M, Pilkington GJ.
School of Pharmacy and Biomedical Sciences, University of Portsmouth, St Michael's Building, Portsmouth, UK. h.rooprai@iop.kcl.ac.uk
Local invasion of neoplastic cells into the surrounding brain is perhaps the most important aspect of the biology of gliomas that precludes successful therapy. Despite significant advances in neuro-imaging, neurosurgery and radiotherapy, the median survival for patients with a malignant glioma is still less than one year. With the increasing knowledge of the biology of brain tumours, derived from cellular and molecular studies, new methods of treatment are being developed with some success. Approaches studied already include anti-invasive, pro-apoptotic and anti-angiogenesis strategies and clinical trials are imminent. In this article we review two new approaches to the management of gliomas: nutraceutical intervention and heterocyclic drugs. The first approach uses a combination of naturally occurring agents, including citrus flavonoids, chokeberry extract, red grape seed extract, lycopene, selenium and red clover extract. These agents can either trigger apoptosis or affect the pathways underlying diffuse invasion. The second approach involves the use of a heterocyclic drug, clomipramine, which selectively triggers apoptosis in neoplastic cells but not in normal glia. The article refers to the results of recent studies performed in our laboratory which suggest that these new approaches can be translated into benefit to patients.
Publication Types:
PMID: 14520549 [PubMed - indexed for MEDLINE]
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2 Effects of dietary supplementation with isoflavones from red clover on ambulatory blood pressure and endothelial function in postmenopausal type 2 diabetes.
Howes JB, Tran D, Brillante D, Howes LG.
Department of Clinical Pharmacology, St. George Hospital UNSW, Kogarah, NSW, Australia.
OBJECTIVE: The aim of this study was to determine whether dietary supplementation with isoflavones from red clover affected ambulatory blood pressure and forearm vascular endothelial function in postmenopausal type 2 diabetic women. DESIGN: Sixteen postmenopausal type 2 diabetics treated with diet or oral hypoglycaemic therapy completed a randomized double-blind crossover trial of dietary supplementation with isoflavones from red clover (approximately 50 mg/day) for 4 weeks compared to placebo. Twenty-four-hour ambulatory blood pressure recordings and forearm vascular responses to acetylcholine, nitroprusside and L-nitromonomethylarginine (L-NMMA) were measured at the end of each treatment period. RESULTS: Mean daytime systolic and diastolic blood pressures were significantly lower during isoflavone therapy compared to placebo (-8.0 +/- 3.4 and -4.3 +/- 1.9 mmHg respectively, p < 0.05). The increase in forearm vascular resistance following L-NMMA was significantly greater during isoflavone supplementation (20.9 +/- 6.5) than placebo (3.7 +/- 2.9 arbitrary units, p < 0.05), suggesting an improvement in basal endothelial function. Plasma lipoproteins, glycated haemoglobin and forearm vascular responses to acetylcholine and nitroprusside did not differ significantly between isoflavone and placebo therapy. CONCLUSION: Isoflavone supplementation from red clover may favourably influence blood pressure and endothelial function in postmenopausal type 2 diabetic women.
PMID: 12940870 [PubMed - indexed for MEDLINE]
3 Phytoestrogens increase the capacity of serum to stimulate prostacyclin release in human endothelial cells.
Garcia-Martinez MC, Hermenegildo C, Tarin JJ, Cano A.
Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Spain.
BACKGROUND: Both the estrogen receptor (ER) alpha and beta isoforms are expressed in the endothelium. The ER beta has been assigned a crucial role in normal vascular wall function. Prostacyclin has been ascribed a beneficial effect on vessel wall physiology. Isoflavones bind with higher affinity to ER beta. We investigated the hypothesis that their administration to postmenopausal women can promote endothelial prostacyclin production. METHODS: Twenty-five healthy postmenopausal women with mild climacteric symptoms received capsules containing 55 mg/day isoflavones derived from soy and red clover for 6 months. Cultured human umbilical vein endothelial cells (HUVECs) were exposed for 24 h to serum collected before the initiation of therapy and then after 3 and 6 months of continuous therapy. Prostaglandin production was measured in culture medium. RESULTS: In the presence of serum obtained after isoflavone treatment, the prostacyclin production increased significantly from 2.7 +/- 0.5 ng/mg protein at baseline to 3.4 +/- 0.7 ng/mg protein at 3 months (p < or = 0.05), and to 3.8 +/- 0.7 ng/mg protein at 6 months (p < or = 0.05 vs. baseline and 3 months' treatment). CONCLUSIONS: Serum obtained from postmenopausal women treated with isoflavones stimulates the capacity to produce prostacyclin by HUVECs in culture, an effect that could contribute to a beneficial cardiovascular effect of phytoestrogens.
PMID: 12848640 [PubMed - indexed for MEDLINE]
4 Anti-androgenic action by red clover-derived dietary isoflavones reduces non-malignant prostate enlargement in aromatase knockout (ArKo) mice.
Jarred RA, McPherson SJ, Jones ME, Simpson ER, Risbridger GP.
Centre for Urological Research, Monash Institute of Reproduction & Development, Monash University, Clayton, Victoria, Australia.
BACKGROUND: Red clover (RC)-derived dietary isoflavones have been implicated as potential preventative agents for the development and prevalence of non-malignant prostate diseases. This study investigated whether dietary isoflavones inhibit prostate growth in vivo in the aromatase knock-out (ArKO) mouse that exhibits lifelong elevation of androgens leading to prostate enlargement. METHODS: Adult (11-week-old) wild-type (WT) and ArKO mice were fed on protein matched isoflavones free (IF) and RC (isoflavone rich) diets for 28 days. Individual prostate lobes and testes were weighed and collected for histological analysis and serum androgens were measured. Responses were compared to castration and estrogen administration to ArKO mice to determine the mechanism of action. RESULTS: ArKO mice fed on IF diet exhibited enlarged prostate lobes and elevated serum androgens compared to WT mice. Following 28 days of RC diet, ArKO VP, AP, and SV weights were reduced to WT weights, although testis and body weights remained unaltered. Stereological analysis of VPs revealed a reduction in all components of the tissue, particularly the lumen. The RC diet reduced ArKO serum testosterone and dihydrotestosterone to WT levels. In comparison to castration and estrogen administration, the dietary isoflavones were shown to be anti-androgenic rather than weakly estrogenic, mimicking responses observed in the castrated ArKO, rather than estrogen treated ArKOs. CONCLUSIONS: This study demonstrates that RC-derived isoflavones have a significant effect on prostatic growth, and are capable of reducing the enlarged non-malignant prostate phenotype of the adult ArKO mouse, by acting as anti-androgenic agents rather than weak estrogenic substances. Copyright 2003 Wiley-Liss, Inc.
PMID: 12746847 [PubMed - indexed for MEDLINE]
Evaluation of the estrogenic effects of legume extracts containing phytoestrogens.5
Boue SM, Wiese TE, Nehls S, Burow ME, Elliott S, Carter-Wientjes CH, Shih BY, McLachlan JA, Cleveland TE.
Agricultural Research Service, Southern Regional Research Center, U.S. Department of Agriculture, New Orleans, Louisiana 70179, USA. sboue@nola.srrc.usda.gov
Seven legume extracts containing phytoestrogens were analyzed for estrogenic activity. Methanol extracts were prepared from soybean (Glycine max L.), green bean (Phaseolus vulgaris L.), alfalfa sprout (Medicago sativa L.), mung bean sprout (Vigna radiata L.), kudzu root (Pueraria lobata L.), and red clover blossom and red clover sprout (Trifolium pratense L.). Extracts of kudzu root and red clover blossom showed significant competitive binding to estrogen receptor beta (ERbeta). Estrogenic activity was determined using an estrogen-dependent MCF-7 breast cancer cell proliferation assay. Kudzu root, red clover blossom and sprout, mung bean sprout, and alfalfa sprout extracts displayed increased cell proliferation above levels observed with estradiol. The pure estrogen antagonist, ICI 182,780, suppressed cell proliferation induced by the extracts, suggesting an ER-related signaling pathway was involved. The ER subtype-selective activities of legume extracts were examined using transiently transfected human embryonic kidney (HEK 293) cells. All seven of the extracts exhibited preferential agonist activity toward ERbeta. Using HPLC to collect fractions and MCF-7 cell proliferation, the active components in kudzu root extract were determined to be the isoflavones puerarin, daidzin, genistin, daidzein, and genistein. These results show that several legumes are a source of phytoestrogens with high levels of estrogenic activity.
PMID: 12670155 [PubMed - indexed for MEDLINE]
6 Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo.
van de Weijer PH, Barentsen R.
Department of Obstetrics and Gynecology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands.
OBJECTIVES: To investigate the effectiveness and safety of a red clover isoflavone dietary supplement (Promensil, Novogen Ltd., Australia) versus placebo on the change in hot flush frequency in postmenopausal women. METHODS: In this randomized, double blind, placebo-controlled trial 30 women with more than 12 months amenorrhoea and experiencing more than five flushes per day were enrolled. All received single blind placebo tablets for 4 weeks and were subsequently randomized to either placebo or 80 mg isoflavones for a further 12 weeks. Efficacy was measured by the decrease in number of hot flushes per day and changes in Greene Climacteric Scale Score. RESULTS: During the first 4 weeks of placebo the frequency of hot flushes decreased by 16%. During the subsequent double blind phase, a further, statistically significant decrease of 44% was seen in isoflavones group (P<0.01), whereas no further reduction occurred within the placebo group. The Greene score decreased in the active group by 13% and remained unchanged in the placebo group. CONCLUSION: In this study, treatment with 80 mg isoflavones (Promensil) per day resulted in a significant reduction in hot flushes from baseline. At the end of the study there was a significant decrease in hot flushes of 44% between the active and placebo group, demonstrating the effectiveness of Promensil in the management of hot flushes.
PMID: 12161042 [PubMed - indexed for MEDLINE]
7 Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women.
Nestel PJ, Pomeroy S, Kay S, Komesaroff P, Behrsing J, Cameron JD, West L.
Baker Medical Research Institute, Melbourne, Australia.
The possibility that the heightened cardiovascular risk associated with the menopause can be reduced by increasing dietary isoflavone intake was tested in 17 women by measuring arterial compliance, an index of the elasticity of large arteries such as the thoracic aorta. Compliance diminishes with age and menopause. An initial 3- to 4-week run-in period and a 5-week placebo period were followed by two 5-week periods of active treatment with 40 mg and then 80 mg isoflavones derived from red clover containing genistein, daidzein, biochanin, and formononetin in 14 and 13 women, respectively, with 3 others serving as placebo controls throughout. Arterial compliance, measured by ultrasound as a pressure (carotid artery) and volume (outflow into aorta) relationship, was determined after each period; plasma lipids were measured twice during each period. Urinary output of isoflavones was also determined. Arterial compliance rose by 23% relative to that during the placebo period with the 80-mg isoflavone dose and slightly less with the 40-mg dose (mean +/- SEM: placebo, .197 +/- .015; 40 mg, .237 +/- 0.007; 80 mg, .244 +/- .014). In the three women receiving continuous placebo, compliance was .16 +/- .022, similar to that during the run-in period for the remaining subjects (.17 +/- .021) [corrected]. ANOVA showed a significant (P = < 0.001) difference between treatments; by Bonferroni multiple comparisons and by paired t test, differences were significant between placebo and 40- and 80-mg isoflavone doses (by paired t test: P = 0.039 for placebo vs. 40 mg; P = 0.018 for placebo vs. 80 mg). Plasma lipids were not significantly affected. An important cardiovascular risk factor, arterial compliance, which diminishes with menopause, was significantly improved with red clover isoflavones. As diminished compliance leads to systolic hypertension and may increase left ventricular work, the findings indicate a potential new therapeutic approach for improved cardiovascular function after menopause.
PMID: 10084567 [PubMed - indexed for MEDLINE]
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