Schellenberg R, Saller R, Hess L, et al. Dose-dependent effects of the Cimicifuga racemosa extract Ze 450 in the treatment of climacteric complaints: a randomized, placebo-controlled study. Evid Based Complement Alternat Med. December 2012;2012:260301. doi: 10.1155/2012/260301.

Menopause can result in bothersome symptoms for women, such as the vasomotor hot flashes and night sweats, along with insomnia and depression. Hormone replacement therapy (HRT), a common treatment for menopausal symptoms, has been linked to an increased cancer risk.¹ Thus, there is a need for nonhormonal alternative therapies for menopausal discomforts. Black cohosh (Actaea racemosa syn. Cimicifuga racemosa) root has been used traditionally by Native Americans to treat a range of ailments, including health problems particular to women.² Previous clinical trials have substantiated its use for the treatment of menopausal symptoms. This randomized, double-bind, placebo-controlled trial investigated the potential alleviation of climacteric symptoms by black cohosh extract Ze 450 (Max Zeller Söhne AG; Romanshorn, Switzerland).

Female patients (≥ 40 years of age) from 4 outpatient clinics in Germany were randomly assigned to 1 of 3 groups taking either 6.5 mg of Ze 450 (1 tablet; low dose) plus 1 placebo tablet, 13 mg of Ze 450 (2 tablets; high dose), or 2 placebo tablets once daily with the morning meal for 12 weeks. Included patients had visited a physician for the treatment of menopausal symptoms. Excluded patients had psychological disorders or were taking related medication, abused alcohol or drugs, were on HRT, had hyperthyroidism or cancer, had ongoing bleeding or myomas (tumors), had been on an "experimental" drug 4 weeks prior to the study, or were pregnant or lactating. Those with internal disorders; those with organ transplants; those who were premenopausal without the use of adequate contraception; those who were intolerant to study treatments; or those who had a body mass index (BMI) of > 30 were also excluded.

Ze 450 is a 4.5-8.5:1 strength 60% ethanol extract of the rhizome and roots of black cohosh. Placebo tablets were described as being "identical" in appearance. Compliance was defined as ≤ 25% of the tablets being given back to the researchers.

Parameters were measured at baseline, 6 weeks, and 12 weeks (visit 1, 2, and 3, respectively). The Kupperman Menopausal Index (KMI) was used to gauge menopausal symptoms. This questionnaire uses a scale for symptoms categorized as none, mild, moderate, or severe, and rated 0-3. Scores were weighted depending on the symptom, and total scores were bracketed into mild (≤ 20), moderate (21-35), and severe (> 35) ranges.

A visual analog scale from 0 mm (best) to 100 mm (worst) was used to assess quality of life (QoL). General laboratory data was collected during the 3 visits, but tests for hormones, pregnancy, and a urinalysis were only done during the baseline visit. The difference in the total KMI scores between groups after the 12-week study was the primary endpoint; secondary outcomes were the KMI subscores for each item, a decrease of ≥ 50% of the total KMI score, the QoL scores, and safety.

In total, 232 patients were recruited, but 52 did not meet the criteria, resulting in a total of 180 patients who were randomly assigned. Their average age was 51.7 years, with an average BMI of 25.2 kg/m². Due to dropouts (n = 3; no reason given) or patients who were lost to follow-up (n = 11), 166 patients were included in the final analysis, with 54 patients in the placebo group, 57 in the low-dose treatment group, and 55 in the high-dose treatment group. Between groups, there was no difference in smoking status; and at baseline, 29 patients had mild menopausal symptoms, 109 had moderate menopausal symptoms, and 28 had severe menopausal symptoms, according to their KMI scores.

After 12 weeks of supplementation, both the low and high doses of Ze 450 resulted in significant decreases in the total KMI scores (-8.47 ± 11.0, P = 0.0003 and -17.0 ± 8.7, P < 0.0001, respectively) as compared to placebo, which allowed a slightly increased score (1.65 ± 9.0). Those consuming the high dose of Ze 450 had significantly decreased KMI subscores for hot flashes, sweating, insomnia, nervousness and irritability, depression, vertigo, weak concentration, joint pain, headache, and palpitations, as compared to those taking the placebo (P < 0.0001 to P < 0.035). It is reported that the amount of decrease associated with the Ze 450 supplementation was predicted by the KMI score at baseline; those with a KMI score between 21 and 35 had a greater improvement with both doses of treatment than those with a KMI score of ≤ 20, although changes in both extract groups as compared to the placebo group were all significantly different (P < 0.001). For those with a KMI score > 35, the decrease in the score was only significant for the high-dose treatment group as compared to the placebo group (P = 0.001).

In premenopausal women, only those in the high-dose Ze 450 group had a significant change in their KMI scores as compared to the placebo group at the endpoint of the study (P < 0.001), but in early- and late-postmenopausal women in both the low- and high-dose treatment groups, there was a significant difference in the KMI scores as compared to the placebo group (P < 0.001 to P = 0.006). There were 69.1% of patients in the high-dose treatment group, 40.4% in the low-dose treatment group, and 7.4% in the placebo group who had a ≥ 50% decrease in their total KMI score. In both dosage groups, QoL significantly improved compared to the placebo group after 12 weeks (P < 0.0001). Of the 21 adverse events reported, all were "nonserious," and only 9 were determined to be "possibly treatment related." Five of these were observed in the placebo group; also, 5 were gastrointestinal in nature, a type previously reported for Ze 450 consumption. From results of the laboratory testing, 3 patients (1 in each group) had high liver enzyme values; 1 was of an unknown cause and the other 2 were likely related to excessive alcohol use.

This study shows that supplementation with the black cohosh product Ze 450 is effective in alleviating menopausal symptoms in various stages, as well as in improving QoL with minimal adverse side effects, with its relative efficacy dependent on the dosage. Interestingly, this study reports a more dramatic improvement in those with more severe symptoms. Limitations mentioned include the relatively brief study period and potential concerns with using the KMI scale. Overall, this study contributes to the knowledge of the effect of dosage on the use of black cohosh extracts for the treatment of menopausal symptoms in different stages of the climacteric.

—Amy C. Keller, PhD

References

¹Rossouw JE, Anderson GL, Prentice RL, et al.; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. July 2002;288(3):321-333.