Red clover may help reduce menopausal symptoms, but additional study is needed.
Red clover contains isoflavone compounds similar to those found in soy. These include biochanin, daidzein, formononetin, and genistein. Although red clover isoflavones show hormonal activity in laboratory experiments, their effects in the human body are less clear.
Studies on whether red clover may help reduce menopausal symptoms are mixed, and additional study is needed to confirm positive effects and safety with long-term use. One study in menopausal women suggests that red clover extract can improve elasticity of major arteries. The loss of elasticity can contribute to increased blood pressure, causing the heart to work harder. However, it is not known if red clover can protect against the development of heart disease, and this will also require more clinical trials.
Red clover extract can stimulate the production of estrogen receptor-positive breast cancer cells in lab experiments. It also stopped the growth of normal prostate cells and increased prostate cancer cell resistance to high-dose radiation. Therefore, patients with estrogen receptor-positive cancers or undergoing radiotherapy for prostate cancer should avoid using red clover.
Purported Uses
To relieve menopause symptoms
Studies on whether red clover may help reduce menopausal symptoms are mixed, and additional study is needed to confirm any positive effects as well as safety with long-term use.
To prevent heart disease in postmenopausal women
A few clinical trials have looked at the effects of red clover on development of risk factors for heart disease in postmenopausal women, with no strong evidence that it helps. Most studies found that red clover had no effect on blood cholesterol or triglyceride levels. One clinical trial found that red clover increased the elasticity of major arteries, which may help prevent a gradual rise in blood pressure that can contribute to heart disease.
Do Not Take If
You have a hormone-sensitive disease such as estrogen receptor-positive breast cancer, ovarian cancer, endometriosis: Red clover may have estrogenic activity and should be avoided or used cautiously by patients with estrogen-sensitive disease.
You are taking methotrexate: A case report suggests red clover may cause toxic effects, including severe vomiting and pain in the upper abdomen.
You are taking warfarin or other blood thinners: Preclinical studies suggest red clover can increase the risk of bleeding. Clinical relevance has yet to be determined.
Side Effects
Case reports
Bleeding around the brain or skull: Related to herbal supplements containing red clover used for menopausal symptoms. In one case, the issue resolved after supplement discontinuation. In another, the patient required intensive medical interventions to resolve issues.
Red clover is a perennial herb traditionally used to treat skin disorders such as psoriasis and eczema, whooping cough, and mastitis. It contains compounds known as isoflavones that act as phytoestrogens. An isoflavone extract is widely promoted as a dietary supplement to relieve menopausal symptoms.
Preclinical studies suggest red clover extract may act as an estrogen agonist and stimulate proliferation of ER-positive breast cancer cells (1). However, the isoflavone Biochinin A inhibited aromatase activity and expression (2) and may therefore confer a protective effect. Isoflavone-enriched extracts have shown neuroprotective effects in human cortical neurons (3)(4) and reduced skin aging in mice by increasing collagen (5).
Clinical data show that supplementation with red clover isoflavones improves menopausal symptoms compared with placebo (7)(8), but systematic reviews are mixed (9)(24)(10). In postmenopausal women, supplementation alleviated vasomotor and menopausal symptoms (18)(25). A meta-analysis of a standardized extract suggests potential reductions in total cholesterol in peri- and postmenopausal women, but studies were heterogeneous (29). Isoflavones may also improve bone loss (11). In a trial involving osteopenic postmenopausal women, a red clover extract rich in isoflavones, aglycones, and probiotics attenuated bone mineral density loss caused by estrogen deficiency and improved bone turnover (26). Dietary isoflavone intake also improved arterial compliance, an index of large artery elasticity which is an important cardiovascular risk factor (12).
Of concern are findings that red clover inhibits the growth of normal prostate cells and increases resistance of prostate cancer cells to high-dose radiation in vitro (15). Patients should consult with their physicians before taking red clover supplements.
Purported Uses
Menopause support
Mechanism of Action
Formononetin, an isoflavone, induced apoptosis in human breast cancer cells by activating the Ras-p38 mitogen-activated protein kinase in ER-positive breast cancer cells (23). It also inhibited proliferation of human osteosarcoma U2SO cells by decreasing expression of miR-375 and Bcl-2, an apoptotic repressor, while increasing Bax, a pro-apoptotic protein (27). The isoflavone Biochanin A inhibited activity and gene expression of aromatase, an enzyme that catalyzes the conversion of androgen to estrogen (2). In addition, it protected dopaminergic neurons against lipopolysaccharide-induced damage by inhibiting microglial activation and proinflammatory factors (3). An isoflavone-enriched fraction showed neuroprotective activity in human cortical neurons as well, possibly due to antioxidant and estrogenic effects (4).
In a murine model, red clover isoflavones reduced skin aging induced by estrogen deprivation following ovariectomy (5).
Contraindications
Patients with hormone-sensitive cancers should avoid red clover because it has estrogenic activity (21).
Red clover may increase effects of anticoagulants and antiplatelet drugs (20).
Red clover causes toxic effects when used with methotrexate (19).
Adverse Reactions
Case reports
Subdural hematoma: In a 65-year-old woman with no other risk factors for bleeding except long-term use of red clover supplements for postmenopausal symptoms. After postoperative re-hemorrhage, an intraoperative thromboelastogram confirmed that antiplatelet effects were more likely than coumarin toxicity. There was no further bleeding after the patient was subsequently treated with tranexamic acid and platelet transfusions (6).
Subarachnoid hemorrhage: In a 53-year-old woman following use of an herbal supplement containing red clover, dong quai, and Siberian ginseng for perimenopausal hot flashes. Symptoms resolved after supplement discontinuation (16).
Herb-Drug Interactions
Anticoagulants / Antiplatelets: Preclinical studies suggest red clover may increase their effects (20). Clinical relevance has yet to be determined. Cytochrome P450 enzymes: Preclinical studies suggest red clover can inhibit CYP 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4, and may interact with substances metabolized by these enzymes (17)(28). Clinical relevance has yet to be determined. Methotrexate: Red clover was reported to cause toxicity, resulting in severe vomiting and epigastric pain, when used along with methotrexate injections (19).
Nestel PJ, Pomeroy S, Kay S, et al. Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women. J Clin Endocrinol Metab 1999;84(3):895-898.
