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Influence of black cohosh (Cimicifuga racemosa) use by postmenopausal women on total hepatic perfusion and liver functions
Influence of black cohosh (Cimicifuga racemosa) use by postmenopausal women on total hepatic perfusion and liver functions In this prospective longitudinal clinical trial, 87 postmenopausal women receiving for 12 consecutive months a daily dose of 40 mg of a dry extract preparation of Cimicifuga racemosa (Klimadynon) for relief of vasomotor symptoms were followed up by evaluation of total hepatic blood flow, assessed by color Doppler ultrasound, as well as prothrombin time and concentration, serum albumin, bilirubin, g-glutamyltransferase, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase. Because no significant changes in total hepatic blood flow or any of the liver functions tested were reported, we concluded that use of C. racemosa for 1 year by healthy postmenopausal women without evidence of liver disease does not seem to influence the liver. (Fertil Steril 2009;92:1780–2. 2009 by American Society for Reproductive Medicine.)
With increasing longevity, a woman is expected to spend more than a third of her lifetime after menopause. Women have menopauseassociated symptoms worldwide (1). Hormone replacement therapy (HRT) is a well-established form of treatment for such symptoms. However, patients and practitioners have undergone a significant change of thought regarding the use of HRT after the publication of two studies focusing on the risks of HRT, the Women’s Health Initiative randomized controlled trial in 2002 and the observational Million Women Study in 2003 (1, 2). Hormone replacement therapy also has been associated with an increased risk of breast cancer (3). Resort to safe and effective nonhormonal alternatives to HRT has acquired growing interest. Black cohosh (Cimicifuga racemosa) is one of the most commonly used herbal remedies for menopausal symptoms that has, for years, enjoyed a very good safety profile (4, 5). However, safety of C. racemosa recently has been questioned after the report of very few, yet serious, cases with manifestations of hepatotoxicity (6–8). In 2006, hepatotoxic reactions were reported in 42 women consuming C. racemosa. However, the European Medicines Agency stated that all discussed cases in the literature and pharmacovigilance reports are poorly documented (9). Clinical trials addressing the alleged claims of C. racemosa–induced hepatotoxicity are seriously lacking; recent concerns have been based essentially on a number of case reports. In this context and given the need to further reappraise safety of C. racemosa in the liver Ahmed Nasr, M.D.a Hanan Nafeh, M.D.b a Women’s Health Center, Department of Obstetrics and Gynecology, Assiut, Egypt b Department of Tropical Medicine and Gastroenterology, Assiut University, Assiut, Egypt Received November 28, 2008; revised March 25, 2009; accepted May 13, 2009; published online June 21, 2009. A.N. has nothing to disclose. H.N. has nothing to disclose. Reprint requests: Ahmed Nasr, M.D., Assistant Professor in Obstetrics and Gynecology, Women’s Health Center, Department of Obstetrics and Gynecology, Faculty of Medicine, Assiut University, P.O. Box 1, 71516 Assiut, Egypt (FAX: 2-088-2368377; E-mail: a_nasr02@lycos. com).
1780
and confirm or refute such claims, we decided to perform this prospective longitudinal clinical trial. After Institutional Review Board approval, 100 healthy postmenopausal women were recruited from among the attendees of the Gynecology Clinic of the Women’s Health Hospital, Assiut University, Assiut, Egypt, in this prospective study and were followed up for 12 months. Eighty-seven women completed the 12-month follow-up period; only those were included in the analysis. Their mean age was 50.21 2.18 years (SD), range 45 to 54 years. Inclusion criteria included an age over 40 years with a lapse of 1 year after the last menstruation, presence of menopause-associated symptoms, absence of gynecologic illness, natural menopause, nonuse of HRT for R6 months before enrollment, acceptance to participate after receiving adequate description of the study design, and accessibility for regular follow-up. The study was presented to women as a safety study of phytoestrogens to alleviate menopausal symptoms. Exclusion criteria included vaginal bleeding, active or chronic liver disease and/or abnormal liver functions, present or past thromboembolic disease, present or past tumors of the breast or uterus, an endometrial thickness >5 mm by transvaginal ultrasonography, and use of alternative, complementary, or herbal medicines for menopausal symptoms within the previous 3 months. The menopausal state was confirmed by a high FSH level in all women. All women gave their written consent to be included in the trial after receiving adequate information about its implications. All women were thoroughly examined clinically, were screened for hepatitis B and C, and underwent abdominal and pelvic sonography. Before using a daily dose of 40 mg dry extract preparation of C. racemosa (Klimadynon; Bionorica AG, Neumarkt, Germany) and for 12 months thereafter, a subjective report on menopausal symptoms, particularly hot flashes, was recorded, and total hepatic blood flow was assessed by color Doppler ultrasound. Moreover, prothrombin time and concentration, serum albumin, bilirubin, g-glutamyltransferase, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase also were measured. The ultrasound equipment used for Doppler studies was the Siemens Sonoline Sienna Ultrasound Imaging System (Siemens, Munich, Germany). This system operates in several modes, a real-time two-dimensional mode, B mode, M mode, spectral Doppler mode, color Doppler mode, and power
Fertility and Sterility Vol. 92, No. 5, November 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2009.05.038
TABLE 1 Clinical characteristics and changes in Doppler-derived parameters of liver perfusion and liver function tests after 12 months of using Klimadynon.
Weight (kg) Systolic BP (mm Hg) Diastolic BP (mm Hg) Prevalence of HF (%) Daily frequency of HF Women with severe HF (%) Hepatic artery blood flow (L/min) Portal vein blood flow (L/min) Total hepatic blood flow (L/min) Total bilirubin (mmol/L) Unconjugated bilirubin (mmol/L) Serum albumin (g/L) AST (IU/L) ALT (IU/L) ALP (IU/L) GGT (IU/L) Prothrombin time (s) Prothrombin concentration (%)
Before use
12 mo after use
P valuea
80.6 3.9b 130.3 7.5b 81.2 5.3b 87/87 (100)c 4.5 1.3b 45/87 (51.7)c 0.81 0.06b 1.43 0.12b 2.38 0.21b 10.1 1.9b 6.4 1.0b 45.8 2.7b 36.3 2.1b 30.9 2.2b 79.3 5.2b 19.6 3.0b 12.7 0.8b 96.8 2.3b
80.4 4.8b 132.5 8.2b 79.8 4.9b 34/87 (39.1)c 1.2 0.3b 2/34 (5.9)c 0.77 0.05b 1.38 0.11b 2.13 0.18b 10.9 1.9b 6.8 1.3b 46.8 3.0b 38.0 2.4b 32.1 2.9b 81.1 6.3b 22.0 2.7b 13.1 0.8b 97.2 2.0b
.3174 .5398 .3246 < .001d < .001d < .001d .4561 .5879 .3654 .8564 .3457 .5641 .7825 .3624 .4677 .2984 .3548 .6856
Note: BP ¼ blood pressure; HF ¼ hot flashes; AST ¼ aspartate aminotransferase; ALT ¼ alanine aminotransferase; ALP ¼ alkaline phosphatase; GGT ¼ gglutamyltransferase. a Student’s t-test or c2 test. b Data are presented as means SD. c Data are presented as numbers and percentages. d Statistically significant difference, before compared with after 12 months of use. Nasr. Correspondence. Fertil Steril 2009.
mode. The scan head is curved array (2.5–5 MHz in the Doppler mode). Doppler measurements were carried out in accordance with standard settings (10). Examinations were carried out by a single examiner after the patient had an overnight fast and a resting period of 15 minutes in the supine position during breath-holding in midexpiration. Examination included evaluation of the portal vein and main hepatic artery. Calculation of the blood flow requires measuring the diameter of the portal vein expressed in centimeters and maximum flow velocity expressed in centimeters per second: Portal blood flow ¼ 22/7 (d)2/4 Vmax/2 60, expressed in milliliters per minute (11). Similarly, hepatic arterial blood flow was measured in the main hepatic artery. The total liver blood flow was taken as the average of three readings of the sum of flow volumes in the common hepatic artery and portal vein (Total liver blood flow ¼ Hepatic arterial blood flow þ Portal venous blood flow). Prothrombin time and concentration were estimated with use of a DiaPlastin kit (12) (DiaMed AG, Morat, Switzerland). Serum albumin, total and direct bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and g-glutamyltransferase were measured with use of colorimetric assay on the automated clinical chemistry analyzer (BM/Hitachi 911; Boehringer, Mannheim, Germany). Microsoft Access (Microsoft Corp., Redmond, WA) was used to collect data that included patient demographic and clinical characteristics before and after treatment. Data were described statistically in terms of mean SD for continuous data and frequencies and percentages for categorical data, where appropriate. Data were analyzed with use of the Statistical Package for the Social Sciences (version 13; SPSS Inc., Chicago, IL). Comparison of quantitative
Fertility and Sterility
variables was done with use of Student’s t-test, Wilcoxon signedrank test, and Pearson’s correlation to study the within-individual correlations between measurements made before and after treatment. For comparing categorical data, the c2 test was performed. A probability value (P value) < .05 was considered statistically significant. No significant changes were noted in weight or in systolic or diastolic blood pressure after 12 months of Klimadynon use. However, a significant reduction in the prevalence, daily frequency, and severity of hot flashes was witnessed after 12 months of use (Table 1). There were no significant changes in Doppler-derived measurements of hepatic artery blood flow, portal vein blood flow, or total hepatic blood flow after 12 months of using Klimadynon (Table 1). Similarly, no significant changes in any of the selected liver function tests were reported (Table 1). Around the globe, millions of women traverse the menopausal transition every year. The World Health Organization projects that approximately 1.2 billion women will be over 50 years of age by the year 2030, which nearly triples the number of women in that age group in 1990 (13). Many women now refrain from using HRT for treatment of menopausal symptoms and are turning to herbal remedies. Unfortunately, in most parts of the world, herbal remedies are not well regulated by federal agencies such as the US Food and Drug Administration. This fact results in considerable variability of content, standardization, dosage, and purity of available products (13). Surveys have shown that more than three quarters of perimenopausal and postmenopausal women in the more affluent societies are current or former users of herbal medicines.
1781
More than two thirds of users describe them as good for one’s health, natural, safe, and more congruent with their values, beliefs, and lifestyles (13). C. racemosa (black cohosh) is a herbaceous perennial plant native to North America and a member of the buttercup family that contains triterpene glycosides, flavonoids, aromatic acids, and other constituents (5). Many studies have reported on the efficacy of C. racemosa in controlling vasomotor symptoms with reduction of hot flashes (5, 14). Black cohosh has been reported to have a positive safety profile when used for up to 6 months; the most commonly reported side effects are mild gastric complaints, which tend to dissipate over time. High doses may, however, cause headaches, vomiting, and dizziness (14). There have been no documented cases of drug interactions with black cohosh (15). Recently, a few alarming case reports of liver failure in women using black cohosh were published (16–18). In 2006, the European Medicines Agency reported on hepatotoxic reactions in 42 women consuming C. racemosa; only four cases were considered reliable, two possible and two probable (9). The US National Institutes of Health has stated recently that there was no known mechanism with biologic plausibility that explains any hepatotoxic activity of black cohosh and added that millions of women have taken black cohosh with very few adverse events reported. They have, however, suggested monitoring of liver functions during the study of black cohosh (19). In the present study C. racemosa was effective in controlling vasomotor symptoms, particularly hot flashes, resulting in a significant reduction in their prevalence, daily frequency, and severity after 12 months (P<.001). This positive finding agrees with those reported by many other studies (5, 14). Regarding hepatotoxic
reactions, more than one potential mechanism of drug-mediated hepatotoxicity was tested. The first was a vascular mechanism through potential compromise of blood flow to the liver, which was assessed by color Doppler sonography, and the second was a direct toxic effect on the liver cells, which was evaluated by a number of selected liver function tests. Putting into perspective the dual blood supply to the liver, blood flow was measured in both the portal vein and common hepatic artery. This is, to the best of our knowledge, the first report on the influence of C. racemosa on liver perfusion. No significant changes were noted in Doppler-derived measurements of hepatic artery blood flow, portal vein blood flow, or total hepatic blood flow after 12 months of using C. racemosa. Likewise, no significant changes in any of the liver function tests were seen after 1-year use of C. racemosa with all levels remaining within the normal range of values. Such findings are in agreement with those of two recent studies (9, 20). However, our findings do not agree with those of a recent animal study stating that C. racemosa exerted hepatotoxicity in vivo and in vitro, eventually resulting in apoptotic cell death in rats (21). On the basis of the results of the present study and the available recent literature, we consider that use of a daily dose of 40 mg of a dry extract preparation of C. racemosa for 12 months by healthy postmenopausal women without history of current or past liver disease and with normal liver functions is safe. We also suggest monitoring of liver functions during treatment in women with abnormal liver functions. It is hoped that this study will be regarded as an added piece of evidence fostering and substantiating safety of the time-tested C. racemosa (black cohosh) in the liver. However, larger randomized controlled trials are needed before generalization of such a statement becomes plausible.
REFERENCES 1. Heinemann K, R€ ubig A, Strothmann A, Nahum GG, Heinemann LA. Prevalence and opinions of hormone therapy prior to the Women’s Health Initiative: a multinational survey on four continents. J Womens Health (Larchmt) 2008;17: 1151–66. 2. van de Weijer PH. Risks of hormone therapy in the 50–59 year age group. Maturitas 2008;60:59–64. 3. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med 2001;344:276–85. 4. Huntley A, Ernst E. A systematic review of the safety of black cohosh. Menopause 2003;10:58–64. 5. Nappi RE, Malavasi B, Brundu B, Facchinetti F. Efficacy of Cimicifuga racemosa on climacteric complaints: a randomized study versus low-dose transdermal estradiol. Gynecol Endocrinol 2005;20:30–5. 6. Chow EC, Teo M, Ring JA, Chen JW. Liver failure associated with the use of black cohosh for menopausal symptoms. Med J Aust 2008;188:420–2. 7. Joy D, Joy J, Duane P. Black cohosh: a cause of abnormal postmenopausal liver function tests. Climacteric 2008;11:84–8. 8. Mahady GB, Low Dog T, Barrett ML, Chavez ML, Gardiner P, Ko R, et al. United States Pharmacopeia
1782
Nasr and Nafeh
9.
10.
11.
12. 13.
14.
15.
Correspondence
review of the black cohosh case reports of hepatotoxicity. Menopause 2008;15:628–38. Firenzuoli F, Goril L, di Sarsina PR. Black cohosh hepatic safety: follow-up of 107 patients consuming a special cimicifuga racemosa rhizome herbal extract and review of literature. Evid Based Complement Alternat Med. In press. Partiquin H, Lafortune M, Burns PN, Dauzat M. Duplex Doppler examination in portal hypertension: technique and anatomy. AJR Am J Roentgenol 1987;149:71–6. Moriyasu F, Ban N, Nishida O, Nakamura T, Miyake T, Uchino H, et al. Clinical application on an ultrasonic duplex system in the quantitative measurement of portal blood flow. J Clin Ultrasound 1986;14:579–88. Quick AJ, ed. Haemorrhagic diseases and thrombosis. Philadelphia: Lee and Febiger, 1966. Geller SE, Studee L. Contemporary alternatives to plant estrogens for menopause. Maturitas 2006;55(Suppl 1):S3–13. Blumenthal M, ed. Cohosh, the ABC clinical guide to herbs. Austin, TX: American Botanical Council, 2002. Pepping J. Black cohosh: Cimicifuga racemosa. Am Journal Health Syst Pharm 1999;56:1400–2.
16. Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Aust 2002;177:440–3. 17. Lontos S, Jones RM, Angus PW, Gow PJ. Acute liver failure associated with the use of herbal preparations containing black cohosh. Med J Aust 2003;179:390–1. 18. Cohen SM, O’Connor AM, Hart J, Merel NH, Te HS. Autoimmune hepatitis associated with the use of black cohosh: a case study. Menopause 2004;11:575–7. 19. National Institutes of Health. Workshop on the safety of black cohosh in clinical studies. Washington, DC: National Center for Complementary and Alternative Medicine, National Institutes of Health Office of Dietary Supplements, 2004. 20. Mazzanti G, Di Sotto A, Franchitto A, Mastrangelo S, Pezzella M, Vitalone A, et al. Effects of Cimicifuga racemosa extract on liver morphology and hepatic function indices. Phytomedicine. In press. 21. Lude S, Torok M, Dieterle S, Knapp AC, Kaeufeler R, Jaggi R, et al. Hepatic effects of Cimicifuga racemosa extract in vivo and in vitro. Cell Mol Life Sci 2007;64:2848–57.
Vol. 92, No. 5, November 2009
With increasing longevity, a woman is expected to spend more than a third of her lifetime after menopause. Women have menopauseassociated symptoms worldwide (1). Hormone replacement therapy (HRT) is a well-established form of treatment for such symptoms. However, patients and practitioners have undergone a significant change of thought regarding the use of HRT after the publication of two studies focusing on the risks of HRT, the Women’s Health Initiative randomized controlled trial in 2002 and the observational Million Women Study in 2003 (1, 2). Hormone replacement therapy also has been associated with an increased risk of breast cancer (3). Resort to safe and effective nonhormonal alternatives to HRT has acquired growing interest. Black cohosh (Cimicifuga racemosa) is one of the most commonly used herbal remedies for menopausal symptoms that has, for years, enjoyed a very good safety profile (4, 5). However, safety of C. racemosa recently has been questioned after the report of very few, yet serious, cases with manifestations of hepatotoxicity (6–8). In 2006, hepatotoxic reactions were reported in 42 women consuming C. racemosa. However, the European Medicines Agency stated that all discussed cases in the literature and pharmacovigilance reports are poorly documented (9). Clinical trials addressing the alleged claims of C. racemosa–induced hepatotoxicity are seriously lacking; recent concerns have been based essentially on a number of case reports. In this context and given the need to further reappraise safety of C. racemosa in the liver Ahmed Nasr, M.D.a Hanan Nafeh, M.D.b a Women’s Health Center, Department of Obstetrics and Gynecology, Assiut, Egypt b Department of Tropical Medicine and Gastroenterology, Assiut University, Assiut, Egypt Received November 28, 2008; revised March 25, 2009; accepted May 13, 2009; published online June 21, 2009. A.N. has nothing to disclose. H.N. has nothing to disclose. Reprint requests: Ahmed Nasr, M.D., Assistant Professor in Obstetrics and Gynecology, Women’s Health Center, Department of Obstetrics and Gynecology, Faculty of Medicine, Assiut University, P.O. Box 1, 71516 Assiut, Egypt (FAX: 2-088-2368377; E-mail: a_nasr02@lycos. com).
1780
and confirm or refute such claims, we decided to perform this prospective longitudinal clinical trial. After Institutional Review Board approval, 100 healthy postmenopausal women were recruited from among the attendees of the Gynecology Clinic of the Women’s Health Hospital, Assiut University, Assiut, Egypt, in this prospective study and were followed up for 12 months. Eighty-seven women completed the 12-month follow-up period; only those were included in the analysis. Their mean age was 50.21 2.18 years (SD), range 45 to 54 years. Inclusion criteria included an age over 40 years with a lapse of 1 year after the last menstruation, presence of menopause-associated symptoms, absence of gynecologic illness, natural menopause, nonuse of HRT for R6 months before enrollment, acceptance to participate after receiving adequate description of the study design, and accessibility for regular follow-up. The study was presented to women as a safety study of phytoestrogens to alleviate menopausal symptoms. Exclusion criteria included vaginal bleeding, active or chronic liver disease and/or abnormal liver functions, present or past thromboembolic disease, present or past tumors of the breast or uterus, an endometrial thickness >5 mm by transvaginal ultrasonography, and use of alternative, complementary, or herbal medicines for menopausal symptoms within the previous 3 months. The menopausal state was confirmed by a high FSH level in all women. All women gave their written consent to be included in the trial after receiving adequate information about its implications. All women were thoroughly examined clinically, were screened for hepatitis B and C, and underwent abdominal and pelvic sonography. Before using a daily dose of 40 mg dry extract preparation of C. racemosa (Klimadynon; Bionorica AG, Neumarkt, Germany) and for 12 months thereafter, a subjective report on menopausal symptoms, particularly hot flashes, was recorded, and total hepatic blood flow was assessed by color Doppler ultrasound. Moreover, prothrombin time and concentration, serum albumin, bilirubin, g-glutamyltransferase, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase also were measured. The ultrasound equipment used for Doppler studies was the Siemens Sonoline Sienna Ultrasound Imaging System (Siemens, Munich, Germany). This system operates in several modes, a real-time two-dimensional mode, B mode, M mode, spectral Doppler mode, color Doppler mode, and power
Fertility and Sterility Vol. 92, No. 5, November 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2009.05.038
TABLE 1 Clinical characteristics and changes in Doppler-derived parameters of liver perfusion and liver function tests after 12 months of using Klimadynon.
Weight (kg) Systolic BP (mm Hg) Diastolic BP (mm Hg) Prevalence of HF (%) Daily frequency of HF Women with severe HF (%) Hepatic artery blood flow (L/min) Portal vein blood flow (L/min) Total hepatic blood flow (L/min) Total bilirubin (mmol/L) Unconjugated bilirubin (mmol/L) Serum albumin (g/L) AST (IU/L) ALT (IU/L) ALP (IU/L) GGT (IU/L) Prothrombin time (s) Prothrombin concentration (%)
Before use
12 mo after use
P valuea
80.6 3.9b 130.3 7.5b 81.2 5.3b 87/87 (100)c 4.5 1.3b 45/87 (51.7)c 0.81 0.06b 1.43 0.12b 2.38 0.21b 10.1 1.9b 6.4 1.0b 45.8 2.7b 36.3 2.1b 30.9 2.2b 79.3 5.2b 19.6 3.0b 12.7 0.8b 96.8 2.3b
80.4 4.8b 132.5 8.2b 79.8 4.9b 34/87 (39.1)c 1.2 0.3b 2/34 (5.9)c 0.77 0.05b 1.38 0.11b 2.13 0.18b 10.9 1.9b 6.8 1.3b 46.8 3.0b 38.0 2.4b 32.1 2.9b 81.1 6.3b 22.0 2.7b 13.1 0.8b 97.2 2.0b
.3174 .5398 .3246 < .001d < .001d < .001d .4561 .5879 .3654 .8564 .3457 .5641 .7825 .3624 .4677 .2984 .3548 .6856
Note: BP ¼ blood pressure; HF ¼ hot flashes; AST ¼ aspartate aminotransferase; ALT ¼ alanine aminotransferase; ALP ¼ alkaline phosphatase; GGT ¼ gglutamyltransferase. a Student’s t-test or c2 test. b Data are presented as means SD. c Data are presented as numbers and percentages. d Statistically significant difference, before compared with after 12 months of use. Nasr. Correspondence. Fertil Steril 2009.
mode. The scan head is curved array (2.5–5 MHz in the Doppler mode). Doppler measurements were carried out in accordance with standard settings (10). Examinations were carried out by a single examiner after the patient had an overnight fast and a resting period of 15 minutes in the supine position during breath-holding in midexpiration. Examination included evaluation of the portal vein and main hepatic artery. Calculation of the blood flow requires measuring the diameter of the portal vein expressed in centimeters and maximum flow velocity expressed in centimeters per second: Portal blood flow ¼ 22/7 (d)2/4 Vmax/2 60, expressed in milliliters per minute (11). Similarly, hepatic arterial blood flow was measured in the main hepatic artery. The total liver blood flow was taken as the average of three readings of the sum of flow volumes in the common hepatic artery and portal vein (Total liver blood flow ¼ Hepatic arterial blood flow þ Portal venous blood flow). Prothrombin time and concentration were estimated with use of a DiaPlastin kit (12) (DiaMed AG, Morat, Switzerland). Serum albumin, total and direct bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and g-glutamyltransferase were measured with use of colorimetric assay on the automated clinical chemistry analyzer (BM/Hitachi 911; Boehringer, Mannheim, Germany). Microsoft Access (Microsoft Corp., Redmond, WA) was used to collect data that included patient demographic and clinical characteristics before and after treatment. Data were described statistically in terms of mean SD for continuous data and frequencies and percentages for categorical data, where appropriate. Data were analyzed with use of the Statistical Package for the Social Sciences (version 13; SPSS Inc., Chicago, IL). Comparison of quantitative
Fertility and Sterility
variables was done with use of Student’s t-test, Wilcoxon signedrank test, and Pearson’s correlation to study the within-individual correlations between measurements made before and after treatment. For comparing categorical data, the c2 test was performed. A probability value (P value) < .05 was considered statistically significant. No significant changes were noted in weight or in systolic or diastolic blood pressure after 12 months of Klimadynon use. However, a significant reduction in the prevalence, daily frequency, and severity of hot flashes was witnessed after 12 months of use (Table 1). There were no significant changes in Doppler-derived measurements of hepatic artery blood flow, portal vein blood flow, or total hepatic blood flow after 12 months of using Klimadynon (Table 1). Similarly, no significant changes in any of the selected liver function tests were reported (Table 1). Around the globe, millions of women traverse the menopausal transition every year. The World Health Organization projects that approximately 1.2 billion women will be over 50 years of age by the year 2030, which nearly triples the number of women in that age group in 1990 (13). Many women now refrain from using HRT for treatment of menopausal symptoms and are turning to herbal remedies. Unfortunately, in most parts of the world, herbal remedies are not well regulated by federal agencies such as the US Food and Drug Administration. This fact results in considerable variability of content, standardization, dosage, and purity of available products (13). Surveys have shown that more than three quarters of perimenopausal and postmenopausal women in the more affluent societies are current or former users of herbal medicines.
1781
More than two thirds of users describe them as good for one’s health, natural, safe, and more congruent with their values, beliefs, and lifestyles (13). C. racemosa (black cohosh) is a herbaceous perennial plant native to North America and a member of the buttercup family that contains triterpene glycosides, flavonoids, aromatic acids, and other constituents (5). Many studies have reported on the efficacy of C. racemosa in controlling vasomotor symptoms with reduction of hot flashes (5, 14). Black cohosh has been reported to have a positive safety profile when used for up to 6 months; the most commonly reported side effects are mild gastric complaints, which tend to dissipate over time. High doses may, however, cause headaches, vomiting, and dizziness (14). There have been no documented cases of drug interactions with black cohosh (15). Recently, a few alarming case reports of liver failure in women using black cohosh were published (16–18). In 2006, the European Medicines Agency reported on hepatotoxic reactions in 42 women consuming C. racemosa; only four cases were considered reliable, two possible and two probable (9). The US National Institutes of Health has stated recently that there was no known mechanism with biologic plausibility that explains any hepatotoxic activity of black cohosh and added that millions of women have taken black cohosh with very few adverse events reported. They have, however, suggested monitoring of liver functions during the study of black cohosh (19). In the present study C. racemosa was effective in controlling vasomotor symptoms, particularly hot flashes, resulting in a significant reduction in their prevalence, daily frequency, and severity after 12 months (P<.001). This positive finding agrees with those reported by many other studies (5, 14). Regarding hepatotoxic
reactions, more than one potential mechanism of drug-mediated hepatotoxicity was tested. The first was a vascular mechanism through potential compromise of blood flow to the liver, which was assessed by color Doppler sonography, and the second was a direct toxic effect on the liver cells, which was evaluated by a number of selected liver function tests. Putting into perspective the dual blood supply to the liver, blood flow was measured in both the portal vein and common hepatic artery. This is, to the best of our knowledge, the first report on the influence of C. racemosa on liver perfusion. No significant changes were noted in Doppler-derived measurements of hepatic artery blood flow, portal vein blood flow, or total hepatic blood flow after 12 months of using C. racemosa. Likewise, no significant changes in any of the liver function tests were seen after 1-year use of C. racemosa with all levels remaining within the normal range of values. Such findings are in agreement with those of two recent studies (9, 20). However, our findings do not agree with those of a recent animal study stating that C. racemosa exerted hepatotoxicity in vivo and in vitro, eventually resulting in apoptotic cell death in rats (21). On the basis of the results of the present study and the available recent literature, we consider that use of a daily dose of 40 mg of a dry extract preparation of C. racemosa for 12 months by healthy postmenopausal women without history of current or past liver disease and with normal liver functions is safe. We also suggest monitoring of liver functions during treatment in women with abnormal liver functions. It is hoped that this study will be regarded as an added piece of evidence fostering and substantiating safety of the time-tested C. racemosa (black cohosh) in the liver. However, larger randomized controlled trials are needed before generalization of such a statement becomes plausible.
REFERENCES 1. Heinemann K, R€ ubig A, Strothmann A, Nahum GG, Heinemann LA. Prevalence and opinions of hormone therapy prior to the Women’s Health Initiative: a multinational survey on four continents. J Womens Health (Larchmt) 2008;17: 1151–66. 2. van de Weijer PH. Risks of hormone therapy in the 50–59 year age group. Maturitas 2008;60:59–64. 3. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med 2001;344:276–85. 4. Huntley A, Ernst E. A systematic review of the safety of black cohosh. Menopause 2003;10:58–64. 5. Nappi RE, Malavasi B, Brundu B, Facchinetti F. Efficacy of Cimicifuga racemosa on climacteric complaints: a randomized study versus low-dose transdermal estradiol. Gynecol Endocrinol 2005;20:30–5. 6. Chow EC, Teo M, Ring JA, Chen JW. Liver failure associated with the use of black cohosh for menopausal symptoms. Med J Aust 2008;188:420–2. 7. Joy D, Joy J, Duane P. Black cohosh: a cause of abnormal postmenopausal liver function tests. Climacteric 2008;11:84–8. 8. Mahady GB, Low Dog T, Barrett ML, Chavez ML, Gardiner P, Ko R, et al. United States Pharmacopeia
1782
Nasr and Nafeh
9.
10.
11.
12. 13.
14.
15.
Correspondence
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Vol. 92, No. 5, November 2009