Long-Term Observational Study Demonstrates Safety of Black Cohosh Extract in Postmenopausal Women

By Donald Brown, ND, Founder and Director, Natural Product Research Consultants, Inc.; Advisory Board, American Botanical Council; President's Advisory Board, Bastyr University, Seattle; Advisor to the Office of Dietary Supplements at the National Institutes of Health. Dr. Brown is a consultant for Nature's Way, Inc.

Source: Rauš K, et al. First-time proof of endometrial safety of the special black cohosh extract (Actea or Cimicifuga racemosa extract) CR BNO 1055. Menopause 2006;13:678-691.

Abstract: In a prospective, open-label, multicenter, multi-national (Czech Republic and Poland) study, the safety of a standardized black cohosh preparation was studied in postmenopausal women. Four hundred women (mean age 56.38 ± 4.77 years) were given 20 mg of black cohosh (Cimicifuga racemosa [L.] Nutt., Ranunculaceae) rhizome extract twice daily. The black cohosh extract used in the trial (BNO 1055, Klimadynon®/Menofem®) was supplied by Bionorica AG (Neumarkt, Germany) and is a dried aqueous/ethanolic (58%, v/v) preparation of the rhizome (standardization specifics are not provided in the paper). The treatment period was 52 weeks.

Data were collected at visit 1 (weeks -4 to -1), visit 2 (day 0 = baseline), visit 3 (four weeks after baseline), visit 4 (week 13), visit 5 (26 weeks), visit 6 (39 weeks), and visit 7 (week 52). The primary outcome of the study was the occurrence of endometrial hyperplasia or more serious adverse endometrial outcome such as carcinoma. Secondary outcome measures included changes in breast density, vaginal bleeding episodes, hormone measures (17β-estradiol, leutinizing hormone [LH], and follicle-stimulating hormone [FSH]), and markers of osteoblast (osteocalcin) and osteoclast (β-CrossLaps). Additionally, serum lipids (total cholesterol [TC], LDL-C, HDL-C, and triglycerides) as well as liver enzymes were measured. The occurrence of adverse events was recorded and the incidence of climacteric complaints was measured using the Menopause Rating Scale II (MRS II).

A total of 375 women completed the entire treatment period of 52 weeks. There were no findings of endometrial hyperplasia or more serious adverse endometrial outcomes reported. In accordance with the result of endometrial biopsies, there was no increase in endometrial thickness found in any subject. Fifty-nine women reported some kind of bleeding episode while taking black cohosh (36, spotting; 8, mild bleeding; 9, moderate bleeding; and 6, strong bleeding). However, in none of these cases were there findings of hyperplasia or development of endometrial thickness more than 5 mm. Serum levels of 17β-estradiol and FSH remained in the postmenopausal range. There were no changes from baseline for breast density with the exception of one woman for whom an invasive breast cancer was diagnosed (this was assessed as not treatment-related). In women with high baseline levels of β-CrossLaps, a significant decrease in the measure was seen over the course of the study (a sign of antiresorptive activity) as opposed to either no change or a slight increase in those with low baseline levels. The reverse was noted for osteocalcin with the high baseline β-CrossLaps group showing a slight increase with black cohosh treatment, whereas while the low β-CrossLaps group showed a significant increase in osteocalcin activity.

Statistically significant, but clinically irrelevant, increases in TC, LDL-C, HDL-C, and triglycerides were found. The LDL:HDL ratio decreased in 64.8% of women and increased in 35.2% at week 52. However, only four women presented a ratio of more than 3.5, the cutoff value for increased risk of coronary heart disease. The upper limits of noncritical values of SGPT, SGOT, and γ-GT were defined as three times above the upper limit of normal ranges. Three women showed SGPT values above this noncritical range with only one continuing to have a high value at week 52. Two women had SGOT levels above the noncritical range with only one remaining elevated at week 52. In seven women, γ-GT values above the noncritical range were found, with only one remaining high at week 52. All changes were reported as nonserious adverse events (AEs) of moderate intensity and were considered unrelated to the study medication. The intensity of climacteric complaints reflected in the total score of the MRS II was significantly reduced by approximately 50% for the entire study group and the four-week weighted score of hot flashes showed a decrease of 80.7% compared to baseline for the entire study group. A total of 752 AEs were recorded. Of these, 414 (55%) were classified as not related to black cohosh and 12 were unclassified. The causal relationship with black cohosh was assessed as possible for 318 (42%) and probable for eight AEs (1%). The intensity of AEs was mild in about 88% of cases.

Comments

Although the safety of black cohosh has been demonstrated in multiple clinical trials, the length of treatment has typically been three months. This is the first long-term study to demonstrate the safety of a standardized black cohosh extract in postmenopausal women. Key is the finding that the Bionorica black cohosh extract BNO 1055 does not stimulate endometrial hyperplasia and does not appear to increase risk of endometrial cancer when used daily for 52 weeks. Also of note is the lack of an effect on breast density. Although there was no placebo group, the long-term effects of black cohosh on hot flashes compared to baseline appear clinically relevant.

I found it interesting that in women with higher levels of osteoclast activity (i.e., bone resorption) at baseline there appeared to be some antiresorptive activity for black cohosh. This differs with an earlier three-month study, which found no effect of the same black cohosh extract on osteoclast activity but clear effects on osteoblast activity.1 Let's hope this warrants follow-up trials in this subset of women to see if black cohosh does in fact have a significant slowing effect on bone resorption.

The lack of significant hepatotoxicity is also noteworthy. Most European phytopharmaceutical companies have added a warning for women who have a history of liver disease taking black cohosh and a warning is now required in Canada as well. Based primarily on case reports out of Australia,2,3 the debate about the hepatotoxic potential of black cohosh continues. Independent safety evaluations have concluded that standardized black cohosh extracts are safe;4 other experts have questioned the reaction (over-reaction?) to the Australian cases, citing problems ranging from lack of analytical verification of products to poor clinical verification of the cause of hepatotoxicity.5 It's also interesting to note that a 2004 workshop on the safety of black cohosh in clinical studies sponsored by the National Institutes of Health found no link between black cohosh and hepatotoxicity.6 Although this long-term safety study appears to suggest lack of hepatotoxicity, it may be prudent for health care professionals recommending black cohosh extracts to choose products that have a track record of safe clinical use (e.g., Klimadynon and Remifemin®) and to regularly monitor patient liver enzymes.

Practice Implications: The use of a standardized black cohosh extract for 52 weeks does not cause endometrial proliferation or negatively effect breast health in postmenopausal women. The results also suggest a longer-term effect on hot flashes and seem to dispel earlier German Commission E guidelines limiting the duration of treatment to six months.7 Although evidence of hepatotoxicity was lacking in this study, health care practitioners who choose to recommend black cohosh may want to routinely monitor liver enzymes in light of the new warnings that are appearing on black cohosh products in Europe, Australia, Canada, and the United States.

References

1. Wuttke W, et al. Effects of black cohosh (Cimicifuga racemosa) on bone turnover, vaginal mucosa, and various blood parameters in postmenopausal women: A double-blind, placebo-controlled, and conjugated estrogens-controlled study. Menopause 2006;13:185-196.

2. Whiting PW, et al. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Austr 2002;177:440-443.

3. Lontos S, et al. Acute liver failure associated with the use of herbal preparations containing black cohosh. Med J Austr 2003;179:390-391.

4. Low Dog T, et al. Critical evaluation of the safety of Cimicifuga racemosa in menopause symptom relief. Menopause 2003;10:299-313.

5. Vitetta L, et al. Black cohosh and other herbal remedies associated with acute hepatitis: Letter to the Editor. Med J Austr 2003;178:411-412.

6. National Center for Complementary and Alternative Medicine and Office of Dietary Supplements, National Institutes of Health. Workshop on the safety of black cohosh in clinical studies. Nov. 22, 2004. Available at: http://nccam.nih.gov/news/pastmeetings/#2004. Accessed Nov. 1, 2006.

7. Blumenthal M, ed. The Complete German Commission E Monographs. Austin, TX: American Botanical Association; 1998:90.