Black Cohosh

Overview
Black cohosh is a traditional herbal medicine with a long history of use by Native Americans that is mostly used for the treatment of menopausal symptoms today. However, it is also used in herbal hormone-balancing formulas, including those for PMS (premenstrual syndrome). Other uses include those for post-operative deficits following ovariectomy, hysterectomy, the treatment of juvenile menstrual disorders, as a substance that promotes menstrual flow (emmenagogue), and for relieving dysmenorrhea or painful menstruation.
The main active constituents of black cohosh are considered to be the triterpene glycosides, and the standardized preparation of Remifemin --the brand that has the most clinical research-- is calculated using the triterpene glycoside, 27-deoxyactein. Other chemical constituents found in black cohosh include quinolizidine alkaloids, formononetin, isoferulic and salicylic acids (low concentrations), tannins, resins, volatile oils, palmitic, gallic, butyric and oleic acids, starches and sucrose (McKenna et al., 2001).
Black cohosh has been studied for cardiovascular and circulatory functions in animals, for osteoporosis in rats and tissue culture, and certain immune and inflammatory functions (McKenna et al., 2001); however, this summary will be limited to reproductive and hormonal functions. A review of the preclinical studies to assess estrogenic activity of black cohosh have produced a range of conflicting results; however, the activity of black cohosh is currently not thought to be due to estrogenic activity. Some of the key preclinical studies are listed below:
•Uterine weight and serum ceruloplasm levels were increased in ovariectomized rats fed an alcoholic extract of black cohosh (Eagon et al., 1997).
•A 25% decrease in luteinizing hormone (LH) was produced by a black cohosh extract (Eagon et al., 1998).
•Black cohosh was shown not to produce a proliferation of estrogen receptor-positive MCF-7 breast cancer cells (Foster, 1999).
•No estrogenic effects of black cohosh were found in mice or rats (Einer-Jensen et al., 1996).
•No significant decrease in LH or other hormonal changes have been found for the new lower recommended doses of Remifemin cases (Schaper and Brümmer GmbH, 1997).
Comments
Black cohosh has become the “super-star” of the women’s health herbs, and will no doubt increase in popularity due to its strong clinical support and the recent controversy and risk in using standard Hormone Replacement Therapy (HRT).
Scientific Support
An open multi-center, multi-clinic, retrospective study was published in Germany in 1982 that assessed Remifemin therapy in 629 females with menopausal complaints. Clear improvements were found in neurovegetative and psychological complaints, and in 40-50% of patients all symptoms abated, or were notably improved in an additional 30-40% (Foster, 1999).
A product surveillance survey of 911 post-, pre-, and perimenopausal women found putative synergistic effects for the combination of black cohosh and St. John’s wort (Hypericum perforatum) (Liske et al., 1997).
A multi-center controlled, randomized, double-blind clinical study compared the results of treatment of two doses of Remifemin in 152 women with neurovegetative climacteric complaints of pre- or postmenopause. There was a statistically significant decrease in the Kupperman Menopause Index and Self-Assessment Depression Scale, and the efficacy was rated as “good” or “very good” by both doctors and patients in 80% of cases (Schaper and Brümmer GmbH, 1997).
The effect of Remifemin on LH and FSH secretion was examined in 110 menopausal women. After 8 weeks of therapy, the LH levels (but not FSH) were found significantly reduced; pulsatile LH release is related to hot flash symptoms (Düker et al., 1991).
In an open study of 60 female patients who had post-operative ovarian functional deficits following hysterectomy (but at least one functional ovary remaining), Remifemin was compared against estriol, conjugated estrogens and an estrogen-gestagen combination. There was improvement in the profile of post-operative ovarian functional complaints, significant declines in the Kupperman Menopause Index, and a moderate but insignificant decline in serum gonadotropin concentration; there was no significant differences in the positive responses between the four groups (Lehmann-Willenbrock and Riedel, 1988).
A 6-month study investigated the conversion of estrogen injection for severe menopausal complaints to a regime of oral Remifemin. Clear improvements were noted in the Menopausal Index, and over half (56%) of the patients required no further injections (Pethö, 1987).
In a randomized, double-blind study of menopausal complaints in 80 women, Remifemin was compared against conjugated estrogens or placebo for 12 weeks of therapy. Compared to the estrogens and placebo, the Remifemin group showed significant increases in the proliferation of vaginal epithelium and improvements of somatic and psychological parameters (Stoll, 1987).
In an open study of 60 women with menopausal symptoms, Remifemin was compared against conjugated estrogens or diazepam. All three therapies showed comparable positive responses in neurovegetative and psychological symptoms; however, only Remifemin and conjugated estrogens produced a proliferation and maturation of the vaginal epithelial cells (Warnecke, 1985).
Two open studies measured the response of black cohosh in women who had either refused hormone therapy or where the hormone therapy had been contraindicated. In both studies, neurovegetative and psychological symptoms were improved (Vorberg, 1984; and Daiber, 1983).
Safety / Dosage
Most studies of black cohosh have used Remifemin (a standardized extract containing triterpene glycosides calculated as 27-deoxyactein; 1 mg/tablet) and the usual dosage was 2 tablets, twice daily. In some studies, a dosage that was two times higher was used, and recent information from the makers of Remifemin suggest that only half the dose is needed for relief of climacteric symptoms (one tablet, twice daily) (Schaper and Brümmer GmbH, 1997).
Other recommended dosage forms have been cited: 40-200 mg dried rhizome, or 0.4-2 mL of a 1:10 60% ethanol tincture; 2-4 mL of a 1:10 60% ethanol tincture; 0.3-2.0 mL of a liquid extract of 1:1 in 90% alcohol; and 0.3 to 2.0 g, 3 times daily, of the decoction of the rhizome (McKenna et al., 2001).
Occasional gastric discomfort is the only noted side effect from clinical studies. Overdoses may produce nausea, vomiting, dizziness, reduced pulse rate, increased perspiration, and premature birth during pregnancy (McKenna et al., 2001).
Although certain estrogens have been associated with the increased risk of female cancers, the actions of black cohosh have been described as “estradiol-like”, and no contraindication has been described between black cohosh and people with estrogen-dependent tumors. There has been some evidence that black cohosh may be helpful (in combination with tamoxifen) in the treatment of breast cancer. Recent opinions about the mechanism of action of black cohosh do not attribute the activity to hormonal (estrogenic) effects (McKenna et al., 2001).
Black cohosh does not have an established safe dosage during pregnancy or labor. The American Herbal Product Association’s Botanical Safety Handbook lists black cohosh as an herb which should not be taken during pregnancy or nursing; however, there have been reports of herbalists using black cohosh along with blue cohosh (Caulophyllum thalictroides) to induce and aid labor (McKenna et al., 2001).
References
1.Daiber W. Klimakterische heschwerden: ohne hormone. Ärztliche Praxis 1983; 35: 1946-1947.
2.Duker EM, Kopanski L, Jarry H, Wuttke W. Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Med. 1991 Oct;57(5):420-4.
3.Eagon CL, Teepe MS, Eagon PK. Medicinal botanicals: estrogenicity in rat uterus and liver. Proceedings of the American Association for Cancer Research 1997; 38: 293.
4.Eagon PK, Swafford DS, Elm MS. Estrongenicity of medicinal botanicals. Proceedings of the American Association for Cancer Research 1998 March; 39: abstract 2624.
5.Einer-Jensen N, Zhao J, Andersen KP, Kristoffersen K. Cimicifuga and Melbrosia lack oestrogenic effects in mice and rats. Maturitas. 1996 Oct;25(2):149-53.
6.Foster s. Black cohosh: Cimicifuga racemosa, a literature review. HerbalGram1999; (45): 35-50.
7.Lehmann-Willenbrock E., Riedal HH. Clinical and endocrinologic examinations of climacteric symptoms following hysterectomy with remaining ovaries. Zentralblatt für Gynäkologie 1988; 110: 611-618.
8.Liske E., Gerhard I, Wüstenberg P. Menopause: herbal combination product for psychovegatative complaints. Therapiewosche Gynäkologie 1997; 10: 172-175.
9.McKenna, D.J.; K. Jones; K. Hughes (eds). Botanical Medicines: A Desktop Reference for the Major Herbal Supplements. 2001; Haworth Press: New York
10.Pethö A. 1987. Klimakterische beschwerden. Ärztliche Praxis 47: 1551-1553, cited in Schaper and Brümmer GmbH, 1995.
11.Schaper and Brümmer GmbH 1997. Remifemin: A Plant-based Gynecological Agent. Scientific Brochure.
12.Schaper and Brümmer GmbH 1995. Remifemin: A Plant-based Gynecological Agent. Scientific Brochure.
13.Stoll W. Phytopharmacon influences atrophic vaginal epithelium. Double-blind study – Cimicifuga vs. estrogenic substances. Therapeuticon 1987; 1: 23-31.
14.Vorberg, G. Therapie kilmaktarischer beschwerden. Erfolgreiche hormonfreie therapie mit Remifemin. Zeitschrift für Allegemeinmedizin 1984; 60: 626-629.
15.Warnecke G. Influencing menopausal symptoms with a phytotherapeutic agent. Medizinische Welt 1985; 36: 871-874.
EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.

Red Clover

Overview
Red clover is a leguminous plant that is high in the plant phytoestrogens, the isoflavones, and has gained popularity as a treatment for menopausal symptoms for this reason. These isoflavones are popular for balancing the hormones in women’s health—especially menopause—because they are thought to act like very weak estrogens. The isoflavones are able to interact with the estrogen receptors on cell surfaces, and in doing so they are thought to both inact a very weak effect of estrogen, and maybe more importantly to compete with the more dangerous forms (higher levels of which cause the adverse effects of estrogen) of estrogen in the body.

The difference between the soy isoflavones and those from red clover is that soy contains only two types of isoflavones, genistein and daidzein, whereas, red clover has four types, genistein, daidzein, biochanin, and formononetin. There are many more studies on the soy isoflavones, but increasing studies on red clover that shows it may deliver the same if not better benefits.

Comments
Red clover seems like another good source of isoflavones, which is just starting to get clinical results. However, as it shares half of the same isoflavones with soy, the benefits should be similar for taking red clover.

Scientific Support
Menopausal Symptoms
Tice et al. (2003) conducted a randomized, double-blind, placebo-controlled study of the effect of two red clover products on menopausal women. The 252 participants were given either Promensil (82 mg total isoflavones daily), Rimostil (57 mg total isoflavones daily) or matched placebo for 12 weeks. The primary outcome measure was the number of hot flashes, while the secondary was adverse events and changes in quality of life. There were no significant differences found between the groups for any of the parameters measured. There was evidence, however, that Promensil reduced the hot flash frequency faster than either Rimostil or placebo.

Red clover extract was clinically tested for its effect on hot flash frequency in postmenopausal women in a randomized, double-blind, placebo-controlled study. The 30 participants were divided into two groups and given either 80 mg isoflavones (from red clover, Pomensil) or placebo daily for 12 weeks. The treatment group resulted in a significant reduction (44%) in hot flashes at the end of the 12 weeks of Promensil treatment (van de Weijer and Barentsen, 2002).

Cholesterol and Insulin Resistance
In order to determine if isoflavones (from red clover) had an effect on cholesterol homeostasis or insulin resistance in premenopausal women, Blakesmith et al., (2003) conduced a randomized, double-blind, placebo-controlled, parallel clinical study. The participants (25) were divided into two groups and given either a) one menstrual cycle of placebo and then three consecutive menstrual cycle of red clover isoflavone supplement (86 mg daily isoflavones) or b) four consecutive menstrual cycles of placebo. There were no significant effects found on cholesterol homeostasis or insulin resistance.

Howes et al. (2000) studied the effect of a red clover isoflavone extract in 66 postmenopausal women with plasma cholesterol levels between 5.0 and 9.0 mmol/l in a placebo-controlled, randomized, double-blind, ascending dose study. The isoflavone extract contained approximately 26 mg biochanin, 16 mg formoneonetin, 0.5 mg daidzein, and 1 mg genistein. The treatment period lasted for 4 weeks. There was no significant difference found between treatment with isoflavones and placebo in plasma lipids in women with moderately high cholesterol levels.

Nestel et al. (1999) studied whether isoflavone intake was able to reduce the elevated risk of cardiovascular disease associated with menopause in a double-blind, placebo-controlled study. Two 5-week periods of active treatment consisted of the administration of 40 mg and then 80 mg isoflavones derived from red clover. The effect on the cardiovascular risk was measured by measuring arterial compliance (the elasticity of the large arteries). Treatment with isoflavones from red clover was found to significantly improve the arterial compliance, and thus potentially reduce the risk of cardiovascular disease after menopause.

Isoflavone Absorption
In a clinical evaluation of the absorption of isoflavones from red clover vs. soy, 14 subjects were studied in a single-blind, randomized, placebo-controlled, crossover clinical trial. The soybean isoflavones and the red clover isoflavones were included in a breakfast cereal and administered as a meal for 2 weeks each. There was no significant difference between the two types of isoflavone sources in the urinary excretion, signifying no difference in absorption (Tsunoda et al., 2002).

Prostate Cancer
Jarred et al (2002) conducted a nonrandomized, nonblind, study to assess if there isoflavone consumption could be linked to prostate cancer incidence. Before surgery, 38 men who had been diagnosed with prostate cancer were given 160 mg daily of red clover derived isoflavones. The tissue upon radical prostatectomy was compared to historical specimens as a control. There were no differences found for serum PSA, Gleason score, serum testosterone, or biochemical factors. There was, however, a significant increase in apoptosis in prostate tumor cells of treated patients, especially in regions of low to moderate-grade cancer. The authors concluded that isoflavones may halt the progression of prostate cancer in low to moderate grade tumors, and that this may be a contributing factor in the lower incidence of prostate cancer in Asian men.

Safety / Dosage
The typical recommended dosage of isoflavones from red clover is 40-80 mg daily. There are no serious side effects associated with red clover extract.

References
1.Blakesmith SJ, Lyons-Wall PM, George C, Joannou GE, Petocz P, Samman S. Effects of supplementation with purified red clover (Trifolium pratense) isoflavones on plasma lipids and insulin resistance in healthy premenopausal women. Br J Nutr. 2003 Apr;89(4):467-74.
2.Howes JB, Sullivan D, Lai N, Nestel P, Pomeroy S, West L, Eden JA, Howes LG. The effects of dietary supplementation with isoflavones from red clover on the lipoprotein profiles of post menopausal women with mild to moderate hypercholesterolaemia. Atherosclerosis. 2000 Sep;152(1):143-7.
3.Jarred RA, Keikha M, Dowling C, McPherson SJ, Clare AM, Husband AJ, Pedersen JS, Frydenberg M, Risbridger GP. Induction of apoptosis in low to moderate-grade human prostate carcinoma by red clover-derived dietary isoflavones. Cancer Epidemiol Biomarkers Prev. 2002 Dec;11(12):1689-96.
4.Nestel PJ, Pomeroy S, Kay S, Komesaroff P, Behrsing J, Cameron JD, West L. Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women. J Clin Endocrinol Metab. 1999 Mar;84(3):895-8.
5.Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) Study: a randomized controlled trial. JAMA. 2003 Jul 9;290(2):207-14.
6.Tsunoda N, Pomeroy S, Nestel P. Absorption in humans of isoflavones from soy and red clover is similar.J Nutr. 2002 Aug;132(8):2199-201.
7.van de Weijer PH, Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas. 2002 Jul 25;42(3):187-93.

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS